Particles and Prejudice: Nanomedicine Approaches to Reducing Health Disparities in Endometrial Cancer.

Despite the clear role of racism in impacting health outcomes, current measures of racism may be inadequate to examine the role of racism in racial disparities in endometrial cancer morbidity and mortality, specifically. The current standard of treatment for endometrial cancer is a combination of surgery, such as laparotomy and/or hysterectomy, chemotherapy, and in select cases radiation and hormone therapies [ 44 ]. One critical challenge that remains in treating endometrial cancer is the limited availability of chemotherapies and the risk for chemoresistant recurrence of the cancer [ 6 , 44 ]. There are only four unique FDA-approved chemotherapeutics for endometrial cancer. The immunotherapies Jemperli (2021) and Keytruda (2019), the kinase inhibitor Lenvima (2021), which must be used with Keytruda, and the hormonal therapy megestrol acetate (1971). Repurposing existing drugs for treating endometrial cancer is one proposed strategy for addressing the therapeutic gap in endometrial cancer. To expand treatment options for individuals with chemotherapeutic resistance, researchers used RL95-2, Hec-1-A, and KLE endometrial cancer cells to evaluate the efficacy of cisplatin in combination with resveratrol, trichostatin A, caffeine, amiodarone, metformin, and digoxin. The RL95-2 cell line was more sensitive to cisplatin than the Hec-1-A or KLE cell lines, and the combination of cisplatin and resveratrol, trichostatin A, caffeine, and digoxin increased apoptosis in the RL95-2 cells [ 149 ]. Lidocaine inhibited proliferation and migration and promoted apoptosis and autophagy of RL95-2 cells compared with human endometrial stromal cells (T HESCs) [ 150 ]. Palmitate, the most abundant saturated fatty acid in the human body, worked in synergy with cisplatin or doxorubicin to increase cell death in RL95-2 and HEC-1-A endometrial cancer cell lines [ 151 ]. Isoalantolactone has been found to suppress cell growth in leukemia, lung, prostate, ovary, melanoma, and colon cancer cells as well as promoting oxidative stress and apoptosis. In HEC-1-B cells, isoalantolactone damaged cell nuclei, altered chromatin condensation, increased reactive oxygen species generation, and inhibited the MEK/ERK signaling pathway thereby inducing apoptosis [ 152 ]. Sugiol, a diterpenoid, significantly reduced proliferation, induced apoptosis and inhibited migration and invasion in Hec-1-B endometrial cancer cells compared with T HESCs [ 153 ]. Another leading strategy in pre-clinical research is using gene modifying technologies such as siRNA or miRNA to impact protein expression in cancer cells. Transfection with siRNA to knockdown Taurine-upregulated gene 1 (TUG1) resulted in significantly decreased migration and invasion and no changes in proliferation in both Hec-1-A and Ishikawa H Type I endometrial carcinoma cells [ 154 ]. B lymphoma Moloney murine leukemia virus insertion region 1 (BMI1) has been linked to cell proliferation, and in HEC-1-B cells overexpression of BMI1 resulted in enhanced proliferation, migration, and invasion following ionizing radiation while also inhibiting apoptosis [ 155 ]. Two novel PARP inhibitors were proposed and evaluated in several cell lines, including the Hec-1-A and Ishikawa H endometrial cancer cell lines where DNA damage, apoptosis, and necrosis was observed. Additionally, in Ishikawa H cells one of the compounds resulted in significantly elevated amounts of cleaved PARP and in Hec-1-A cells both compounds resulted in significant increases [ 156 ]. Immortalized cell lines available for endometrial cancer research represent Type I and Type II cancers as well as metastatic and non-metastatic cancers ( Table 1 ). Several of these cell lines are also capable of forming tumors in murine models, which allows for in vitro and in vivo comparisons on efficacy. Traditionally, genetic diversity and ancestry have been disregarded in in vitro analyses. However, there may be benefit in considering these factors, particularly in endometrial cancer which has such stark racial disparities. Although in vitro models cannot account for racial disparities due to socioeconomic, environmental, and/or structural racism, they can address genetic disparities. Recent work has utilized genotyping data and estimated the origins of several cancer cell lines, highlighting the genetic diversity [ 157 ]. Modeling the endometrium in vitro remains a challenge as traditional tissue culture plastic is a poor substrate for cell development. Importantly, the endometrium is one of the only tissues in the adult human body that undergoes frequent overturn in a normal state [ 158 ]. As such, in vitro models for endometrial cancer can originate using healthy patient-derived endometrial cells [ 159 ]. Many models exist, including those derived from synthetic biomaterials and those derived from patient samples. Biomaterials that mimic the extracellular matrix (ECM) of gynecological tissues can improve in vitro analyses [ 7 , 160 ]. The guiding principle in endometrial cancer is to capture the cancer-stromal cell interactions, most often achieved using a blend of collagen I and Matrigel for the matrix [ 161 , 162 ], with success also demonstrated using poly(ethylene glycol) (PEG) hydrogels [ 163 ]. Additionally, accurate capitulation of the basement membrane in the endometrium appears critical in the success of neoplastic and non-neoplastic models alike [ 164 ]. Biomaterial models include the traditional two-dimension (2D) culture on tissue culture plastic, novel 2D culture on hydrogels, novel 3D culture on hydrogels, transwell plates, and microporous scaffolds [ 161 ]. ECM models that have been confirmed for endometrial cancer include a on which both endometrial epithelial and stromal cells were able to attach and proliferate [ 165 ]. Furthermore, another group explored combinations of collagen I, collagen III, collagen IV, collagen V, tenascin C, hyaluronic acid that promoted endometrial epithelial cell attachment and growth [ 164 ]. Alternatively, patient-derived models include patient derived organoids (PDO), patient-derived xenografts (PDX), and patient-derived explants (PDE). A notable difference between PDO and PDX models is that PDX models take longer to grow because the biopsy is placed in an in vivo model [ 1 , 166 ]. Patient-derived explants (PDEs) are formed by dissecting fresh tumor tissue obtained during hysterectomy and culturing these cells prior to drug response testing. As with PDO and PDX models, these PDE models can predict drug sensitivities and resistances [ 166 ]. PDO screening was tested in a 70-year-old patient presenting with high-grade serous endometrial carcinoma positive for HER2. This model showed no differences in the PDOs treated with the platinum-containing chemotherapeutic carboplatin and the untreated control. However, the PDO model was more sensitive to paclitaxel, gemcitabine, and topotecan compared with the platinum (carboplatin) and paclitaxel regimen. Additionally, these agents did not cause the same cell death in non-malignant tissues derived from the same patient [ 1 ]. Berg et al . demonstrated the same chemosensitivity and resistance to carboplatin, paclitaxel, and their combination in PDOs in vitro and organoid based PDX models [ 167 ]. Guerrero, et al . highlighted racial and ethnicity diversity in basic and applied cancer models ( Figure 4 ), including the genetic diversity in cell lines and tumor samples available at the National Cancer Institute Patient-Derived Models Repository, which includes PDX models and in vitro patient-derived cell cultures (PDCs) [ 168 ]. Perhaps not surprisingly 46.1% of cell lines have no information on race or ethnicity, 37.7% were isolated from Whites, 11.6% from Asians and 4.2% from Blacks [ 168 ]. These differences become even more drastic when one investigates tumor samples, of which there is no racial/ethnic no data for 62.86% of samples, 36.19% were from Whites and 0.95% were from Blacks [ 168 ]. In endometrial cancer specifically, genomic characterization of established endometrial cancer cell lines highlight the differences in endometrial cancer types and patients and in turn exemplify the need for robust pre-clinical investigations ( Table 1 ) [ 169 ]. 105 paired carcinoma tissue samples and NNTs were collected from patients with Type I endometrial cancer who had not received chemotherapy or radiation therapy prior to their biopsy and revealed that there is overexpression of TUG1 in Type I endometrial carcinoma, which correlates to a low overall survival rate [ 154 ]. Traditional chemotherapy is a powerful tool to treat advanced endometrial cancer, and there have been numerous scientific advances in evaluating the efficacy of this therapy. However, it remains challenging for those in rural and low socioeconomic environments to access life-saving chemotherapy. Additionally, we know that chemotherapy is not a “one size fits all” treatment for cancer patients. Advances such as directives towards personalized medicine and targeted tumor therapies can improve the existing landscape of endometrial cancer treatment. There are two forms of targeted therapy, the first is therapy that targets specific mutations in cancers. The second form of targeted therapy utilizes targeted drug delivery systems (TDDSs), which are often nanoparticle-based methods for increasing the therapeutic efficacy of drug delivery to tumor tissues [ 179 ]. Upregulated genes and proteins are a common target for therapeutics because the receptors can potentially improve tumor-specific targeting [ 180 ]. Downregulated genes and proteins do not offer the same advantages; however, they can be exceptionally useful in diagnostics [ 181 ]. Improvements on the current standard of care include advances in biomarkers for personalized medicine, nanoparticle-based targeted drug delivery systems (TDDSs), and nanoparticle-based reduction of post-surgical infections [ 182 ]. There are two forms of targeted therapy, the first is therapy that targets specific mutations in cancers. The second form of targeted therapy utilizes targeted drug delivery systems (TDDSs), which are often nanoparticle-based methods for increasing the therapeutic efficacy of drug delivery to tumor tissues ( Figure 5 ) [ 179 ]. Improvements on the current standard of care include advances in biomarkers for personalized medicine, nanoparticle-based targeted drug delivery systems (TDDSs), and nanoparticle-based reduction of post-surgical infections [ 182 ]. Metals and metal oxide nanomaterials hold promise as antineoplastic agents. Magnetic hypothermia with Fe 3 O 4 nanospheres had increased uptake by gynecological cells, including Hec-1-A cells, when decorated with polyetherimide and folic acid compared to those without folic acid [ 183 ]. Folic acid is commonly overexpressed in endometrial cancer tumors, therefore the potential of this receptor-mediated targeting method to preferentially target endometrial cancer cells is promising [ 184 ]. Additionally, these nanospheres did not have significant impacts on cell viability [ 183 ]. Four endometrial cancer cell lines: Ishikawa H, KLE, Hec-1-A, and Hec-1-B were investigated for potential antioxidant properties of copper nanoparticles (CuNPs). CuNPs induced cell death in a dose-dependent manner in all aforementioned endometrial cancer cell lines with an IC50 value of ~350 μg/mL [ 185 ]. Abraxane is a 130 nm albumin-bound form of paclitaxel that eliminates the need for solubilizing paclitaxel in Cremophor EL and has been approved in metastatic breast cancer and non-small cell lung cancer [ 186 ]. A limited case study for two patients with papillary serous endometrial cancer indicated that treatment with abraxane reduced hypersensitivity reactions associated with paclitaxel (Cremophor EL) [ 187 ]. A more extensive study of 37 patients with gynecological cancers supported these findings [ 130 ]. Recent reports indicate that the combination of these strategies is more effective than either strategy alone. For example, Ebeid et al . demonstrated that synergistic targeting of the triple angiokinase molecular inhibitor and nanoparticle-loaded paclitaxel was more effective than either agent alone at treating endometrial cancer using Ishikawa, Hec50Co, and KLE cells both in vitro and in murine tumors [ 8 ]. This research group later demonstrated that PD98059 (MEK1/2 inhibitor) works in synergy with paclitaxel to improve cell cycle arrest and thus apoptosis in vitro and in vivo when delivered to HEC50co cells and tumors in PAMAM-coated PLGA-PEG nanoparticles compared to soluble PD98059 [ 188 ]. Several receptors including CD44, hyaluronic acid binding proteins (HABP1 and HABP2), bind hyaluronic acid. When these receptors are upregulated in cancer tissue, hyaluronic acid is a promising substrate for active tumor targeting. Increased expression of CD44 in tumor tissues results in increased cell migration and metastasis initiation, thus cancers expressing increased CD44 also tend to be more invasive [ 189 ]. Furthermore, studies have confirmed increased expression of CD44 in certain endometrial cancers [ 189 - 191 ]. In the Ishikawa H endometrial cancer cell line, the cells were characterized as CD44 low and therefore hyaluronic acid uptake was low compared with those cells classified as CD44 high [ 192 ]. One study combined the metal oxide nanoparticle ZnO with hyaluronic acid for active targeting of CD44 receptors [ 193 ]. The nanococktail as it was called also included a cell penetrating peptide and the chemotherapeutic doxorubicin. Studies indicated that the nanococktail induced cell death in the SCC-7 (mouse squamous cell carcinoma) and COS7 (African green monkey kidney fibroblast-like cell) cell lines as well as mice bearing SCC-7 tumors. HABP1 functions in tumorigenesis, progression, invasion, metastasis, and wound repair [ 6 , 194 ]. Increased expression of HABP1 correlates with poorer prognoses in endometrial cancer [ 195 ]. When endometrial cancer tissue was compared with benign endometrial lesions and normal endometrium, HABP1 had significantly higher expression [ 194 ]. Increased expression of HABP1 correlates with poorer prognoses in endometrial cancer [ 195 ]. When endometrial cancer tissue was compared with benign endometrial lesions and normal endometrium, HABP1 had significantly higher expression [ 194 , 195 ]. PTEN somatic mutations have been reported in several types of gynecological tumors. PTEN inactivation is present in endometriosis and endometrial hyperplasia and may be considered an early event in cancer development, particularly in endometrioid (Type I) tumors [ 196 ]. The most common targetable pathway associated with PTEN is the PI3K pathway. Using small interfering RNA (siRNA) knockdown of homeobox A11 (HOXA11), Kong et al. repressed apoptosis and promoted proliferation, migration, and invasion in Ishikawa endometrial cancer cells. Knockdown also increased cisplatin resistance in endometrial cancer cells via the PTEN/AKT pathway [ 197 ]. These results suggest that HOXA11 is critical to anti-neoplastic activity in endometrial cancer. On the contrary, microRNA (miRNA) upregulation of miR-135a resulted in increased proliferation, migration and invasion in Hec-1-B and Ishikawa cells after treatment with cisplatin, and it was confirmed that miR-135a influenced the expression of PTEN and p-AKT [ 198 ]. TP53 is one of the most common mutations in cancers, and in endometrial cancer mutations are common in more aggressive subtypes [ 199 ]. Thiel et al . demonstrated the advantage of adding bevacizumab to chemotherapy on improving progression-free survival of endometrial cancer patients [ 199 ]. Furthermore, when selecting for patients with p53 mutations, bevacizumab showed marked improvements compared to those patients that did not receive bevacizumab [ 199 ]. The use of biomarkers improves diagnosis and treatment of cancers, including endometrial cancers. In cancer, biomarkers are often gene mutations, such as BRCA1/2 , TP53 , PTEN , PIK3CA, PLAC1, DACH1, and HABP2 [ 200 - 203 ] [ 20 , 204 , 205 ]. As exhibited in the previous section, some of these biomarkers can be used for targeted therapy, whereas others such as PLAC1 or DACH1, are not yet clinically targetable for improved treatment although both have been implicated in endometrial cancers [ 200 - 203 ]. Additionally, the value of biomarkers for determining prognosis remains under debate [ 206 ]. Using clinical and genomic data from patients with endometrial cancer and whole-exome sequencing, significantly higher mutations in DACH1 were experienced in Kentucky women compared with The Cancer Genome Atlas (TCGA) data [ 203 ]. The amount of tissue resected from a hysterectomy varies based on how far the cancer has spread. A partial hysterectomy only removes the uterus, whereas a total hysterectomy removes the uterus and cervix. One or both ovaries and fallopian tubes along with surrounding lymph nodes may also be removed. Given the nature of this invasive surgery, the risk for post-surgical infection and thus further complications remains. The mechanisms that regulate wound healing are closely related to the hallmarks of cancer [ 207 ]. Chemotherapy and radiation therapy can also slow surgical healing time [ 208 ]. Toczek et al . reviewed improved wound healing following hysterectomy for endometrial cancer using metallic nanoparticles [ 182 ]. Intrauterine adhesive antibacterial microneedle patches designed with a porous structure and loaded with CD34 + human endometrium-derived adventitial cell spheroids were effective agents for wound healing [ 209 ]. In cancer research, in vitro models using immortalized cell lines provide an excellent first-step for investigating the potential for repurposing existing drugs and for novel drug delivery systems. Unfortunately, many approaches are stuck in this in vitro phase and have not advanced to any in vivo models. Additionally, these cell lines do not represent all molecular and ancestral variations in the human population. As such, patient-derived models often offer better models, but are difficult to develop and implement, and still do not completely encapsulate the full range of variations in the human population. Furthermore, when considering the validity of pre-clinical in vitro models, tissue culture plastic has long-been accepted as a poor substrate for modeling cells. Bioengineering approaches to developing better substrates, such as including collagen-containing hydrogels because collagen is a major component in cellular ECM. That said, cellular ECM is not all made equal and the best model for one cancer site does not necessarily match the best model for another cancer site [ 7 ].

Uterine cancer is the 9 th most common type of cancer in the U.S and represents 3.4% of all new cancer cases. It is estimated that there will be 65,950 new cases in 2022 [ 19 ]. The female reproductive system includes the uterus, fallopian tubes, ovaries, cervix, and vagina ( Figure 1 ). Uterine cancers originate in the uterus but can metastasize to neighboring organs. In females, uterine cancer accounts for 7% of all new cancer diagnosis and is the fourth most common cancer behind breast, lung/bronchus, and colon/rectum cancer [ 19 ]. Approximately 90% of uterine cancers are cancers of the uterine lining, also called the endometrium. All other forms of uterine cancer, including serous adenocarcinoma and carcinosarcoma, make up the remaining 10% of cases [ 20 ]. Uterine cancer is the second most common cancer in women, second only to breast as of 2019 [ 19 ]. Approximately 90% of uterine cancers are cancers of the uterine lining, also called the endometrium. All other forms of uterine cancer, including serous adenocarcinoma and carcinosarcoma, make up the remaining 10% of cases Historically histological classification of endometrial cancer has considered as either Type I or Type II. However, these classifications do not encompass all molecular intricacies the cancer may possess. Alternative classifications exist such as classifications based on mutations: (a) DNA polymerase epsilon (POLE) ultramutated, (b) microsatellite instability (MSI) hypermutated, (c) copy-number low endometrioid tumors with high frequency of CTNNB1 mutations, and (d) copy-number high TP53 mutations [ 21 , 22 ]. Using cell line analysis, Kojima et al . determined that the presence of claudin 6 corresponded to malignant phenotypes both in vitro and in in vivo xenografts [ 23 ]. The Cancer Genome Atlas (TCGA) includes information on endometrioid carcinoma, endometrial serous carcinoma, and carcinosarcoma, and indicates that the PI3K-AKT pathway is highly mutated in endometrial cancers as well as mutations in CTNNB1, KRAS, POLE , and TP53 mutations [ 16 ]. Many novel approaches use mutations as targets in drug delivery, which are all discussed in detail in section 4.3 . Additionally in uterine cancer, there are “low-risk” tumors, which are low-grade endometrioid tumors, and “high-risk” tumors, which include uterine carcinosarcoma, high-grade endometrioid, high-grade clear cell, and high-grade serous tumors. The low-risk tumors have a much higher five-year survival rate than high-risk tumors (83% versus 44%, respectively), and less invasive treatment strategies, where chemotherapy and radiation therapy typically are not required [ 24 ]. Although comprehensive staging has been debated in low-risk endometrioid tumors as surgery is usually curative, integrating both clinical and molecular data improved predictive performance to 97% [ 25 ]. Treatment for low-risk tumors is often hysterectomy with bilateral salpingo-oophorectomy and lymph node staging [ 22 ]. Recently, a pre-clinical investigation for sentinel lymph node detection in low-risk endometrial cancers with carbon nanoparticles (NPs) and indocyanine green showed successful detection in 94.4% of patients using NPs versus only detection in only 15% of patients with dye alone [ 26 ]. Additional recommendations for first-line treatment of uterine cancers were outlined in 2020 by the Society of Gynecologic Oncology’s Clinical Practice Committee [ 3 ]. Most notably, the review committee recommended that estrogen receptor status be considered in Stage 3 and Stage 4 patients [ 3 ]. Notably, estrogen receptor targeting has been widely investigated in solid tumors, including those of the breast, ovarian, and endometrial tissues. For instance, Lewinska et al developed a PAMAM dendrimer conjugated with lapatinib and fulvestrant for dual targeting of HER2-positive and estrogen receptor (ER)-positive breast cancers, respectively [ 27 ]. Notably, endometrial cancers in pre-menopausal women often exhibit ER-positivity [ 28 ], thus making this a potentially translatable therapy. The global burden of disease (GBD) studies began in 1991 as a collaboration between academia and the World Health Organization [ 29 ]. Multiple groups have identified nanomedicine as an avenue to reduce the overall GBD [ 30 , 31 ], utilizing the advanced knowledge of different types of nanocarriers and delivery routes ( Figure 2 ). One parameter that is useful in comparing different countries is the socio-demographic index (SDI), which is a summary measure that identifies where countries are on the spectrum of development. This metric is based on several factors including income per capita, average educational attainment, and fertility rates. When using SDI, one can make inferences on the impact of the country’s relative development on the global burden of disease. In uterine cancer, the World Cancer Research Fund International reports global incidence rates are 8.7 per 100,000 women compared with the SEER-reported data of 27.8 per 100,000 women in the United States. In 2020, Poland had an incidence rate comparable with the United States at 26.2 cases per 100,000 women. Globally, in areas with a higher socio-demographic index (SDI), women have a much higher rate of endometrial cancer. From 1978-2013, data collected showed that United States, Canada, and Europe had significantly higher rates of diagnosis of endometrial cancers compared to middle income countries, including South Africa, India, and others with similar economic developmental status, had much lower rates between one third and one sixth of the rates in the United States, Canada, and Europe [ 32 ]. On the contrary, when comparing the Franco-Caribbean territories of Guadeloupe, Martinique, and French Guiana, endometrial cancer incidence rates were similar or lower compared with mainland France [ 33 ]. Mortality rates were combined for all both cervical and endometrial cancer; therefore, mortality could not be determined. In other parts of the Caribbean, a 2009 study showed that regionally, endometrial cancer was responsible for 6.4% of cancer deaths in women, the fourth highest cancer mortality rate in this region [ 34 ]. Ancestry may impact the observed incidence rates in addition to SDI. The racial classification of “Black” includes all individuals with African ancestry, and thus is more inclusive than the “African American” term, which refers to those who are descendants of enslaved people. Black American women are more likely to be diagnosed with the more aggressive Type II histological subtype of endometrial cancer, which has the poorer prognosis and higher mortality rate. In the United States, the rate of new uterine cancer diagnosis is 27.8 per 100,000 persons for all races according to SEER. Three races have incidence rates higher than the national average, with non-Hispanic Blacks having the highest incidence rate of 29.3 per 100,000 persons, American Indian and Alaskan Natives have an incidence rate of 28.1 per 100,000 persons, and non-Hispanic Whites have an incidence rate of 28.0 per 100,000 persons. Hispanics and Asian/Pacific Islanders have incidence rates below the national average or 26.0 per 100,000 persons and 22.6 per 100,000 persons, respectively. Over the past almost 50 years, there has been great variability in the incidence rate of uterine cancer. It was at its highest in 1975 at 36.3 per 100,000 persons, from there it steadily decreased to 23.8 in 1988. Between 1988 and 2008, the rate fluctuated between 23.8 and 25.8. From 2009 until 2020, the incidence rate has been steadily increasing to 28.3 cases per 100,000 persons. Between 2010 and 2019, it increased at a rate of 0.6% per year. With this increase in incidence rate, it is projected that uterine cancer will become the third most common female cancer by 2030 [ 35 ]. The risk of developing endometrial cancer increases with age. The probability of developing endometrial cancer is highest in females over 70 (1.3%). Between the ages of 60 to 69, there is a 1% chance. From the age 50 to 59, there is a 0.6% chance of developing endometrial cancer. The probability of developing endometrial cancer is lowest (0.3%) in females 49 years old or younger [ 19 ]. The average age at the time of diagnosis is 63 years old. The two age ranges that have the highest percent of new cases are 55-64 and 65-74 years of age, which accounts for 33.2% and 29.7% of new diagnoses, respectively. When combined with new diagnoses among females who are 45-55 years old (14.7% of all new cases), over 75% of all new diagnoses occur among females aged 45-74 years old. Further, the Unites States, Canada, and Europe showed that the age-standardized incidence rate for postmenopausal women were between 4 and 20 times higher than premenopausal women. Looking from 1990-2019, the age-standardized incidence rate increased in all age groups. This was most seen in premenopausal women with a change from 2.26 per 100,000 women in 1990 to 3.27 per 100,000 women in 2019 [ 36 ]. Post-menopausal women aged 50-69 experienced an increase in incidence from 31.22 per 100,000 women in 1990 to 36.57 per 100,000 women in 2019 [ 36 ]. In women over 70, the incidence increased from 41.1 per 100,000 women in 1990 to 44.0 per 100,000 women in 2019 [ 36 ]. In the countries with higher SDI, the rates of incidence for endometrial cancer had increased at a much higher rate, however, the mortality rates were much lower in these areas. Although the mortality rates of most cancers have declined since the 1970s, the mortality rates in uterine cancers have not [ 37 ]. Mortality rates within the United States average 5.1 deaths per 100,000 persons. However, Non-Hispanic Black women have mortality rates of 9.1 deaths per 100,000 persons according to 2016 – 2020 SEER data. From 2016-2020, the mortality rate was 5.1 per 100,000 females. It is projected that 12,550 American females will die from uterine cancer in 2022 which will account for 2.1% for all deaths related to cancer. Uterine cancer is the 15 th deadliest cancer in the US. In females specifically, uterine cancer accounts for 4% of all cancer deaths and is the sixth most common cause of cancer death in females behind lung, breast, colorectal, pancreatic, and ovarian cancer [ 37 ]. Black women have the highest morality rate of any race at 9.1 per 100,000 persons. This rate is almost twice as high as any of the other races, where the next highest mortality rate occurs for non-Hispanic White women of 4.6 per 100,000 persons. American Indian/Alaska Natives have the third highest mortality rate at 4.5 per 100,000 persons. Hispanics have a rate of 4.3 per 100,000 persons. Asian/Pacific Islander have the lowest rate at 3.5 per 100,000 persons. The average age of death from endometrial cancer is 70 years old with the majority (over 75%) of the deaths occurring between the ages of 55-84. The age range with the highest percentage of deaths is 65-74 accounting for 34.1% of deaths. The other two ranges, 55-64 and 75-84, account for almost the same amount with 21.8% coming from females aged 55-64 and 23.0% coming from females aged 75-84. Additionally, in communities of Black women with endometrial cancers earlier stage at diagnosis was the best predictor for increased five-year survival [ 38 ]. Family income, financial well-being of the family, and BMI were also strong predictors for survival [ 38 ]. Mortality rates based on income can be broken down further by looking at the difference in rates based on poor versus affluence, where these are based on county-level poverty status [ 19 ]. Poor refers to a county where 21.18% to 53.95% of the population are in poverty. Affluent counties are signified by having 1.81% to 10.84% of the population are in poverty [ 19 ]. From 2012 to 2016, there was a higher mortality rate of 5.3 per 100,000 for all races who were in a poor county versus an affluent county. The affluent county mortality rate was 4.6 per 100,000. For White women, the rate of mortality was lower at 4.3 per 100,000 in poor counties versus affluent counties at 4.5 per 100,000. In this five-year period, Black women have a mortality rate almost double that of White women; only the poor counties have a higher mortality rate of 8.9 when compared to the affluent counties mortality rate of 8.2 [ 19 ]. The average rate of increase of the mortality from uterine cancer between 2011 and 2020 was 1.6% per year in the United States. Over the past 50 years, the highest mortality rate of uterine cancer occurred in 1975 and 1976 at 5.3 per 100,000. From 1977 until 1997, the rate decreased to 4. From 1998 until 2009 the rate bounced between 4.1 and 4.2. After 2009, there was a steady increase in the death rate until it reached the current rate of 5.1 in 2020. The five-year survival rate has had very little variability since 1975. In 1975, the survival rate was at its highest at 88.7%. From then until 1981, there was a decrease in survival rate to 80.5. It then increased slightly to 84.3% in 1985. From 1985 to 2000, the survival rate had variability ranging from 81.8% to 86.4%. From 2001 until 2014, the rate fluctuated about two percent, bouncing between 83.3% and 85.4% but mainly staying around 84%. Endometrial cancer has a five-year survival rate of 81.3%. Endometrial cancer that is found early at stage 1, which is localized in the uterus, accounts for 67% of the cases. Like most cancers, earlier diagnosis is associated with better survival rates. However, unlike other cancers with high mortality rates, such as breast and colorectal cancers, no available screening mechanisms exist. Although there are no existing screening mechanisms for endometrial cancer, advances in biosensing may impact early detection in a positive way. Surface enhanced Raman scattering was used to detect ovarian and endometrial cancers from liquid biopsy using tumor extracellular vesicles (EVs) on a scaffold made from microscale biosilicate embedded with silver NPs [ 39 ]. Porphysomes were used to guide tumor resection in a rabbit model with good predictive results of the primary tumor site, lymph node metastasis, and abdominal metastasis [ 40 ]. Localized endometrial cancer has a five-year survival rate of 94.9% from 2012-2018. If the cancer has spread to the regional lymph nodes, it is categorized as regional. Cancers that are regional at the time of diagnosis account for 20% of all cases with a five-year survival rate of 69.8% which is about 15% lower than localized endometrial cancer. Cancer that has metastasized to surrounding organs and/or tissues is staged as distant. Distant endometrial cancer only accounts for 9% of all endometrial cancer and has a significantly lower survival rate of 18.4%. A very small percentage (3%) of endometrial cancer cannot be staged and it categorized as “unknown”. Unknown endometrial cancer has a five-year survival rate that falls between regional and distant at 52.2%. In the Caribbean, several countries have mortality rates that exceed the United States average, including Grenada with 9.5 per 100,000 women, St. Vincent and the Grenadines with a mortality rate of 8.0 per 100,000 women, and Trinidad and Tobago with a mortality rate of 7.6 per 100,000 women. In Trinidad and Tobago, the average age of diagnosis was 63.9±12.1 years as of 2009 [ 34 ], comparatively the median age of diagnosis in the United States is 63 years. This same study showed that Africa had the highest mortality- to incidence-rate ratio (MIR) worldwide with an MIR of 0.80. Worldwide, the global MIR was 0.61 indicating that roughly 61% of women diagnosed with endometrial cancer would die from the cancer or complications relating to the cancer [ 34 ]. The lowest MIR came from parts of Europe and North America with MIR values as low as 0.57. Risk factors for endometrial cancer can be divided among three different categories: (a) reproductive, (b) hormonal, and (c) all else. In fact, one report links incidence rates to changes in hormone therapy and obesity ( Figure 2 ) [ 41 ]. Reproductive risk factors include early age at menarche, late onset of menopause, infertility, and anovulation [ 42 , 43 ]. Hormonal risk factors include excess estrogen, excess progesterone, and unopposed estrogen. Additionally, conditions such as polycystic ovarian syndrome (PCOS) and obesity are considered hormonal risk factors [ 43 , 44 ]. Risk factors that do not fit into either of these categories include hereditary syndromes such as Lynch syndrome and Cowden syndrome [ 44 ], as well as environmental factors such as chemical exposure [ 45 ] or socioeconomic status [ 46 ]. A pooled analysis of factors including obesity, age at menarche, and diabetes among others revealed associations with type II tumors [ 47 ]. Thus, the risk factors for Type II endometrial cancers may be multi-faceted and require a broader approach in analyses. Obesity is a current public health crisis in the United States and a global epidemic [ 48 ]. Obesity is typically marked by a body mass index (BMI) over 30 kg/m 2 and a BMI from 25 kg/m 2 – 30 kg/m 2 is considered overweight [ 49 ]. Elevated BMI is one of the strongest risk factors for developing endometrial cancer in both the United States and in Europe, particularly Type I endometrial tumors [ 50 ]. In fact, obesity may account for up to 40% of the observed endometrial cancer incidence [ 41 , 42 ], while another report estimated up to 57% of endometrial cancer cases being attributable to obesity [ 51 ]. It should not be discounted that BMI was developed as a Eurocentric measurement and has since been shown to be inaccurate for several populations, including African, Polynesian, and Asian people [ 52 ]. Decoupling “excess body weight,” which could be in the form of fat, muscle, or water and “excess body fat,” which is restricted to adipose tissue, is important in future considerations of the impact of obesity on endometrial cancer incidence and mortality. Furthermore, accounting for a waist to hip ratio, which accounts for abdominal adipose tissue, was not a predictive factor for increased endometrial cancer risk whereas individual waist and hip measurements were [ 42 ]. Obesity is also closely related and therefore compounded with other risk factors for endometrial cancer, including type II diabetes, insulin resistance, and unopposed estrogen [ 24 , 53 ]. Type II diabetes mellitus (T2DM) is the seventh leading cause of death in the United States and disproportionately affects non-White minorities, including Asian Americans, Hispanic Americans, and Black Americans [ 54 - 56 ]. Furthermore, despite risk factors being well-defined for T2DM, many high-risk minority individuals are not screened and subsequently live with undiagnosed T2DM [ 55 ]. Many patients with T2DM are also overweight or obese, thus all risk factors discussed in the previous section apply. Data from the National Health Interview Survey (NHIS) suggested that observed increases in diabetes from 1990 – 2008 may have contributed in part to increased endometrial cancer incidence, independent of obesity [ 41 ]. In fact, studies suggest that when BMI is controlled, the link between T2DM and endometrial cancer is no longer significant [ 57 , 58 ]. In T2DM, patients either have impaired insulin production or impaired response to insulin. Insulin plays an important role in cell signaling and proliferation, which can further complicate endometrial cancer outcomes [ 59 ]. Impaired response to insulin is known as insulin resistance, which may be connected to endometrial cancer by chronic inflammation and increased C-reactive protein [ 60 ]. This theory explains the observed higher burden of T2DM in Black adults because Black adults have significantly higher levels of C-reactive protein than White adults [ 56 ]. The link between type I diabetes (T1D), which is the form where the pancreas ceases to produce insulin, and endometrial cancer has yet to be established. However, a meta-analysis, a significant positive association between T1D and endometrial cancer was found [ 61 ]. Metformin is typically the first line treatment for T2DM in the United States. This drug has demonstrated antineoplastic effects, although the effective dose for antineoplastic activity has been debated [ 62 ]. Metformin is a biguanide, which is a class of drugs that work via preventing the liver from converting fats and amino acids into glucose as well as activating the enzyme AMP-activated protein kinase (AMPK) to promote cellular response to insulin. In carcinogenesis, AMPK induces p53 phosphorylation to prevent cell invasion and metastasis [ 60 , 63 ]. As such, many research efforts into the utility of metformin as an anticancer agent in melanoma, lung cancer, endometrial cancer, breast cancer, and colorectal cancer have been conducted [ 64 ]. Retrospective analysis of clinical outcomes has also demonstrated that metformin decreases the mortality rate of endometrial cancer compared with non-metformin users [ 65 ]. Pre-clinical studies in vitro demonstrated inhibited cell proliferation, migration, and invasion in the two Type I endometrial cancer cell lines Ishikawa and RL95-2 [ 66 ]. Another study demonstrated that metformin decreased expression of the PD-L1 protein in Ishikawa and RL95-2 cells [ 67 ]. Pre-clinical models have also demonstrated efficacy in treatment and chemoprevention, but not for metformin as an effective prophylactic treatment to reduce endometrial cancer risk [ 57 ]. One notable pre-clinical model utilized cell culture in a high glucose environment to mimic the hyperglycemia experienced in diabetes. In this model, metformin significantly inhibited proliferation even though the cell line used is resistant to metformin. Furthermore, nanoparticle encapsulation of the pyruvate dehydrogenase kinase 1 (PDK1) inhibitor improved inhibition in vitro and in a diabetic mouse model in vivo [ 68 ]. In clinical studies, metformin and progesterone combination therapy showed significant improvements in treatment [ 69 ]. This is particularly important as progesterone is the hormone that typically opposes estrogen, yet another risk factor for endometrial cancer [ 70 ]. Further, an in vivo study with metformin and paclitaxel, a chemotherapeutic, revealed that the combination reduced progestin resistance in endometrial cancer cells [ 60 ]. Hormonal links to endometrial cancers are significant, particularly the estrogen/progesterone balance. Excess estrogen, or unopposed estrogen, may stem from a variety of causes and is considered a risk factor in Type I endometrial cancer [ 59 ]. In the case of unopposed estrogen, there is a two-factor cause: estrogen levels are elevated, and progesterone levels are reduced [ 70 ]. Excess estrogen often has internal causes, which include obesity, being under the age of 12 at menarche, or over the age of 55 at the onset of menopause [ 42 ]. However, excess estrogen may also have external causes, such as hormone replacement therapy to manage symptoms of menopause or to treat other cancers [ 71 ]. Fortunately, in hormone replacement therapy, estrogen-only methods have been mostly phased out and as such do not remain risk factors for endometrial cancer [ 42 ]. In women that had not received any postmenopausal hormone therapy (i.e., exogenous estrogen) there was a 441% increase in endometrial cancer risk for obese women [ 53 ]. In women successfully treated for endometrial hyperplasia solely with progestin-containing IUDs had decreases in estrogen receptor, progesterone receptor, and progesterone receptor isoform B levels [ 72 ]. Additionally, expression of FOXO1, a tumor suppressor gene in the endometrium, mRNA levels was predictive of progression following IUD therapy, where upregulated FOXO1 was predictive of no progression [ 72 ]. Polycystic ovary syndrome (PCOS) is a disease where unopposed estrogen arises from reduced production of progesterone in anovulatory cycles [ 24 ]. A meta-analysis of women under 54 with PCOS revealed higher rates of gynecological cancers, but not ovarian or breast cancers [ 73 ]. Additionally, a separate meta-analysis revealed that women with PCOS were approximately three times more likely to develop endometrial cancer than women without PCOS [ 74 ]. Although the link between successful management and treatment of PCOS with the risk of developing endometrial cancer has yet to be explored, early studies indicate that nanoparticle-based treatment of PCOS with curcumin is highly effective [ 75 ]. Furthermore, there is emerging work on NP therapeutics for PCOS which could ultimately impact gynecological cancer incidence. Alwan and Al-Saeed demonstrated that biofabricated silver NPs were an effective treatment against inflammatory responses induced by PCOS in female rats [ 76 ]. Additionally, selenium NPs have been demonstrated as an effective treatment for PCOS in rats [ 77 ]. Recent updated recommendations for treating endometrial cancer included the recommendation that all tumors be screened for Lynch syndrome via mismatch repair status, determined by germline mutations in the MLH1 or MSH2 mismatch-repair gene [ 16 ], and/or microsatellite instability [ 3 ]. One potential screening mechanism is via liquid biopsy analyses [ 78 ]. Another potential method reported by Barrow et al , is using quantum dots for multiplex staining to diagnose Lynch Syndrome [ 79 ]. The median age of diagnosis of endometrial cancer for women with Lynch syndrome is 48 years, which is much lower than the general population’s 63 years of age [ 16 ]. Cowden syndrome is a rare, heritable disorder originating in germline mutations of the PTEN gene. that results in non-cancerous growths called hamartomas and an increased risk of cancer formation [ 80 ]. Studies on Cowden syndrome and endometrial cancer are significantly fewer than those evaluating Lynch syndrome. In a review of 371 women with Cowden syndrome or Cowden-like syndrome with endometrial carcinoma, most lesions were endometrioid carcinoma [ 81 ]. Targeting PTEN is further discussed in Section 4.2.1 . Incidence and mortality rates of endometrial cancer continue to rise, despite advances in modern medicine. On top of this, Black women have much higher rates of death from endometrial cancer and are at higher risk for certain co-morbidity factors. Endometrial cancer is classified using biopsies of the tumor tissue, however, in low-risk cases, full classification is not always conducted. Comprehensive molecular classification of endometrial cancer can improve treatment options, and several pre-clinical studies are underway to advance the breadth of options ( Section 4 ). When considering patient treatment, co-morbid conditions such as T2DM and obesity are not often included in decision-making for treatment plans. As such, individuals with comorbidities may not receive the best treatment. Furthermore, these co-morbidities are often neglected in pre-clinical models, and very few animal models have been developed to successfully model these co-morbidities in cancer [ 82 ]. However, medications that can potentially treat both cancer and T2DM, in particular metformin, have been investigated and shown promising early results [ 64 - 67 ].

Endometrial carcinomas show the greatest racial disparity among all cancers where the five-year survival for non-Hispanic Black women is 62% versus 83% for non-Hispanic White women, even when access to care is a controlled variable [ 24 , 83 ]. As such, recent work has called for more efforts to examine social determinants of health, and racism, specifically, to explain racial/ethnic disparities in endometrial cancer morbidity and mortality [ 84 , 85 ]. Indeed, experiences of racism may exacerbate racial disparities in other health outcomes, such as lupus activity [ 86 ], obesity [ 87 ], cancer or tumor risk [ 88 ], HIV and sexually transmitted infections [ 89 ], low birthweight [ 88 , 90 ], and COVID-19 fatality rates [ 91 - 93 ]. Biomedical research has often treated race as a biological marker that may be used to determine risk for various medical outcomes, including tumor incidence rates, comorbidity (such as obesity and T2DM), and mortality [ 85 ]. In this section, we treat race as socially constructed and learned [ 85 , 94 , 95 ]. Thus, although racial group categories are often organized around salient characteristics, such as skin color, they are also arbitrary in nature and vary across cultures [ 96 ]. In the United States, race, particularly concepts of race tied to the study of Black people, is informed by a history of chattel slavery that has systematically sought to devalue and dehumanize Black people and protect White people’s dominant status [ 95 , 97 ]. Furthermore, direct results of this dominant perception result in biased advances in technologies and testing of novel technologies [ 98 , 99 ]. Racism, then, can be understood as a system of policies, beliefs, and practices that privileges one group (e.g., White people) over another (e.g., Black people) [ 95 , 100 ]. As we outline in Figure 3 and throughout this manuscript, racism likely impacts endometrial cancer morbidity and through individual, systemic, and cultural forms of racism, as is the case with other disease outcomes [ 101 ]. We highlight in this model that racism and racist beliefs are often cumulative in nature, building on lower-level interactions and all contributing to an overall negative effect, such as endometrial cancer morbidity and mortality. Importantly, the lowest level effects at the intra-individual level include primary and secondary epigenetic and disease outcomes. The downstream effects are then enhanced, often negatively for racial minorities, by interpersonal interactions, systems policies and structures, cultural beliefs, and changes over time. This cumulative effect is also, evidenced both the research on racism as a stressor that results in physiological changes to the body [ 102 - 105 ], as well as work chronicling myths about Black people’s pain tolerance [ 106 , 107 ]. Further, the effects of interpersonal and/or systemic racism on health outcomes are concomitant and mutually reenforcing [ 68 , 72 ]. For example, individual beliefs and attitudes inform individuals’ support for policies that may systematically disadvantage minoritized racial/ethnic groups, just as social policies including segregation and slavery may promote and reinforce racist beliefs [ 94 , 107 , 108 ]. Further, individuals need not actively and explicitly endorse racism to support structural forms of racism or encourage displays of racism in others. Individuals are often highly motivated to maintain group inequality [ 109 , 110 ], even if they do not believe themselves to be personally prejudiced [ 94 ]. Perhaps the most used measure to assess individual experiences of racism is the Everyday Discrimination Scale, which assesses general experiences of discrimination. Other commonly used measures include indices of race-related stress, and the schedule of racist events, which assesses racist events throughout respondents’ lifetimes, and the incidence of specific events within a given period [ 111 ]. These measures are gathered via self-report questionnaires and thus are subject to the methodological issues often present in self-report data [ 112 ]. However, all three measures are commonly used in the social and biomedical sciences, including cancer research [ 113 ], and generally exhibit good psychometric properties [ 84 ]. Generally, measures such as the everyday racism scale assess experiences of interpersonal forms of discrimination [ 114 ]. However, some measures, such as the schedule of racist events, may assess perceived structural forms of racism, including whether institutions are likely to discriminate against respondents [ 111 ]. In addition, examinations of the role of structural racism in health often consider other variables, including county-level poverty, county-level segregation, distance to healthcare centers, and county-level educational attainment [ 19 , 90 ], which can be directly tied to racist policies [ 84 ] [ 95 ], and have been shown to directly impact health outcomes [ 84 , 90 , 107 , 108 ]. Racial bias exists in many healthcare technologies often as a “ghost variable” [ 115 ]. Examples of racial bias in health technology occur from idea conception to efficacy evaluations [ 116 ]. Some technologies which have suffered from racial bias include pulse oximeters [ 99 ], infrared (forehead) thermometers [ 117 ], and X-rays [ 118 ]. As a result, the FDA drafted updated guidance in 2022, the first time in 25 years, for diverse representation in clinical trials, including that trial demographics must be reported [ 119 ]. This is a significant change as less than half of all United States clinical trials from 2010 - 2020 reported race/ethnicity enrollment data, and of those that do minorities are underrepresented [ 13 , 14 ]. According to the most recent census data, individuals identifying as a single race who may or may not also identify as Hispanic, the United States is 75.8% White, 13.6% Black, and 6.1% Asian. Additionally, the United States was 18.9% Hispanic or Latinx. One quantitative study reported that overall clinical trial enrollment was 84.2% White versus 7.3% Black, 3.4% Asian, and 2.8% Hispanic or Lantinx [ 120 ]. Another quantitative analysis of oncology-specific FDA approvals indicated participation of 76.3% White, 3.1% Black, 18.3% Asian, and 6.1% Hispanic [ 14 ]. These data indicate that clinical trials do not accurately represent the racial diversity of the United States population, and that oncology trials are even poorer than others. Additionally, another report indicated that these data were even worse for women where only 2% of participants in oncology trials were Black women compared with 84% White women [ 121 ]. Several critical barriers to minority participation in cardiovascular clinical trials were identified as: (1) lack of trust, (2) lack of comfort, (3) lack of information, (4) lack of time and resources, and (5) lack of awareness [ 108 ]. These barriers have been confirmed in subsequent oncology-specific reports [ 122 ]. The original report also included steps towards mitigating these critical barriers, such as building trust and improving communication between investigators and potential participants [ 123 ]. Other reports specific to oncology have confirmed some of these critical barriers, such as lack of time and resources [ 122 ]. Importantly, even though clinical trials often offer the best option for treatment, individuals participating in clinical trials must still determine how they will pay for treatment and how they will be transported to the clinical site [ 122 ]. This produces a burden on those of lower socioeconomic status and/or in rural locations. Understanding the downstream effects of having underrepresented populations in clinical trials and pre-clinical development of treatments is critical when considering the development of nanomedicine and novel treatment strategies. Racist policies, such as red-lining, which prohibited Black families from obtaining mortgages in predominantly White areas, have contributed to large wealth gaps between Black and White [ 124 , 125 ]. These policies and other forms of systemic racism have kept Black families in largely segregated neighborhoods, with less community wealth, and poorer access to education and healthcare [ 19 , 108 ]. Some work also suggests that red-lining relegated Black families to areas with higher exposure to environmental toxins [ 101 ]. Further, systemic forms of racism independently contribute to Black-White disparities in birth weight and gestational age [ 90 ], and COVID-19 morbidity and mortality among other disease outcomes [ 91 ]. Experiencing racism and other forms of bias may also prompt feelings of vigilance, a coping mechanism in which individuals anticipate rejection or victimization [ 87 , 126 , 127 ]. Racism-related vigilance have been associated with increased blood-pressure [ 128 ], poorer sleep [ 126 ], and greater obesity [ 87 ]. Indeed, Martz and colleagues found that even when personal experiences of discrimination and disease risk factors were controlled, merely hearing about others’ experiences of discrimination was associated with greater lupus disease activity among Black women [ 86 ]. Research on other stigmatized groups, such as lesbian, gay, bisexual, and transgender individuals, similarly shows that vigilance related to fears of discrimination and violence is associated with poorer health outcomes [ 127 ]. Laboratory and naturalistic studies suggest that racism and racism-related vigilance affects health outcomes by eliciting physiological stress responses, implicating both the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic and autonomic nervous system (ANS) reactivity in response to experiences of racism [ 103 - 105 ]. Activation of both systems is an adaptive response to acute stressors [ 129 , 130 ]. However, chronic stress and activation of these systems may lead to greater “wear and tear” on the body, resulting in poorer mental and physical health [ 131 ], suppression of immune responses [ 132 ], and earlier onset of disease [ 131 - 133 ]. Racism may impact health outcomes through several avenues [ 101 ]. Black patients may have fewer positive experiences with physicians and receive poorer care than their White counterparts. For example, physicians are more likely include negative descriptors of Black patients, such as “agitated” and “non-compliant” in patient notes [ 134 ]. Alarming numbers of doctors also believe that Black people are inherently less likely to experience pain than are White people--beliefs that were used to justify the physical and medical abuse of enslaved Black people [ 106 , 107 ]. It is, therefore, perhaps unsurprising that Black patients are often undertreated for pain [ 106 , 107 ], including gynecological conditions, such as endometriosis and uterine fibroids [ 135 ]. Intersectionality theory suggests that Black women’s experiences are affected by interlocking systems of oppression relating to both their gender and racial identities [ 136 ]. As such, Black women may feel the negative effects of both racism and sexism and may also experience distinct forms of oppression related to both their race and their gender. For example, modern gynecological practices are informed by the medical abuse of Black enslaved women’s bodies [ 85 , 137 ]. Black women—particularly if they were also poor or disabled—were more likely to experience state-sanctioned forced sterilizations than their White peers [ 138 ]. There are also specific stereotypes of Black women that are related to sexual behavior, and which affect their reproductive health. For example, Black women are often perceived as promiscuous, sexually available, and animalistic (e.g., the jezebel) and as poor, uneducated, young single mothers who use sex and men for money (e.g., welfare queen, gold digger) [ 139 ]. Individuals may perceive Black women as having more sexual partners, being less likely to use birth control regularly, more likely to have children, more likely to be on public assistance, and having less education compared with White women [ 140 ]. Pregnant Black women are also perceived as less likely to have baby’s father involved [ 141 ]. Black women may anticipate negative experiences with physicians [ 137 ], and therefore, may delay seeking medical care [ 141 ]. Additionally, these women may experience greater anxiety about seeing a doctor [ 142 ], greater pregnancy related stress [ 137 ], and greater psychological distress, even when factors, such as life-stressors are controlled [ 143 ]. As such, we may expect that implementing nanomedicine that can reduce the number of required physician interactions may have a positive benefit in Black women’s health. Despite the clear effects of gendered forms of racism on Black women’s health outcomes, there is very little work that explicitly examines it. Indeed, most work that examines the effects of racism on health, even among Black women, uses measures, such as the everyday racism scale [ 84 , 86 , 87 , 126 , 144 ]. However, this measure likely better captures racism experienced by Black men than Black women, as Black men are viewed as more prototypical of Black people compared with Black women [ 145 , 146 ], and more scholarly and media attention focused on Black men than Black women [ 91 , 147 , 148 ]. There is very little work on gendered racism, particularly as it pertains to women’s reproductive health [ 137 , 140 ]. There are no studies, to our knowledge that specifically examined how gendered racism impacts Black women’s endometrial cancer morbidity and mortality. However, as gendered racism affects physician interactions with Black women [ 142 ], structural barriers to treatment [ 108 ], and is a social-evaluative stressor similar to others implicated in more severe disease across a wide variety of disorders [ 103 - 105 ], there is a critical need to understand the role of intersectional forms of bias Black women’s health. We, thus, follow other calls that advocate for more rigorous, intersectional research on racial disparities in endometrial morbidity and mortality [ 85 ].

Despite having similar incidence rates, Black women have almost twice the mortality rate from endometrial cancer than White women in the United States. Additionally, Black women are more likely to suffer from certain co-morbidity factors and experience both systemic and interpersonal racism. Even given the strong evidence for racial and gender disparities, current pre-clinical models do not adequately reflect the biological makeup of these individuals. Government organizations have issued calls to improve racial and gender disparity, such as the FDA’s newest draft guidance for diverse representation in clinical trials [ 119 ], and the National Institutes of Health’s policy on including sex as a biological variable in study design [ 210 ]. Despite these agency-level recommendations, science still requires significant advancements to address racial and gender disparities, as well as modeling endometrial cancer. Genetic variations extend to the cellular level and may impact the relevance of immortalized cell lines on the ultimate translation to clinical treatments. Cell line classification is important when considering whether an established treatment is relevant to Type I endometrial cancer, Type II endometrial cancer, both or neither. Furthermore, germline mutations may influence the efficacy of existing and novel treatments, therefore this is important to consider both in study design and in patient diagnosis. In addition to genetic variation, phenotypic variations (i.e., race) also exist. Racial disparities may be exacerbated by systemic and interpersonal racism, which influences the quality and type of care Black women receive. Further, much of the work examining the role of racism in health outcomes, may fail to capture specific forms of racism that black women experience by virtue of their racial and gender identities [ 114 , 137 , 140 ]. These disparities are not limited to cancer, and in fact may be experienced throughout a Black woman’s lifetime, thus resulting in long-standing effects by the time she is diagnosed with endometrial cancer, which has an average age of diagnosis if 63 years. Recent research in endometrial cancer has addressed repurposing existing drugs, developing novel drug delivery systems for existing drugs, and/or including nanoparticles in treatment. Furthermore, biomaterials engineering has identified ways in which to improve in vitro cell culture models. By using substrates that mimic the native extracellular matrix of the cells, researchers can gain confidence in their results. These efforts have been made in reference to gynecological cancers, including endometrial cancer, other cancers, and other areas of research.

Endometrial cancer is the most common gynecological malignancy worldwide and the most common form of uterine cancer [ 1 , 2 ]. Incidence and mortality rates have been rising domestically since the 1970s, contrary to observed trends in most cancers [ 3 , 4 ], and continue to rise at approximately 1.3% annually [ 5 ]. The racial disparities in mortality rates of endometrial cancer are stark. The five-year data (2015 – 2019) from the Surveillance Epidemiology and End Results (SEER) Explorer and SEER databank break down incidence and mortality rates and trends in uterine cancer based on race as defined by the United States Social Security Administration. These data indicate that Black women are twice as likely to die from endometrial cancer than any other racial group, despite having similar incidence rates. This indicates the presence of a racial inequity in Black women’s mortality from endometrial cancer. Such inequities are preventable discrepancies in incidence and/or mortality of disease. Throughout this article, we discuss differences between Black women and other racial groups as they pertain to healthcare and disease incidence. We also explain how advances in nanomedicines and understanding cancer on a molecular level can help us address this inequity. The rise in both incidence and mortality rates in endometrial cancer raise concerns for advances in diagnosis and treatment. Currently, there is no screening method for endometrial cancer and treatment for advanced stage endometrial cancer is lagging with only four unique FDA approved chemotherapeutics currently in use [ 6 , 7 ]. When endometrial cancer is diagnosed early (stages 1 – 2), hysterectomy can be completely curative. However, when not diagnosed until later (stages 3 – 4), radiation and/or chemotherapy are required, yet they remain highly ineffective [ 8 ]. One budding strategy to combat this is the use of nanomedicine. Patients with advanced endometrial cancer are often offered surgery in conjunction with chemotherapy and/or radiation therapy [ 9 - 11 ]. However, chemotherapeutic treatment of endometrial cancer is often restricted to clinical trials and the limited number of approved therapeutics eliminates the ability to assess individual needs [ 1 ]. Additionally, there is racial and gender inequity in enrollment of United States clinical trials, further exacerbating mortality rate disparities [ 12 - 14 ]. Furthermore, there exists a push to move towards personalized medicine. Personalized medicine utilizes advances in science to identify which treatments may have the best efficacy in a patient prior to the beginning of treatment, and many of these strategies leverage nanomedicine [ 15 ]. For endometrial cancer, these considerations include the histological subtype and gene mutations. Endometrial cancer is also divided into two histological subtypes, Type I and Type II [ 6 ]. Type I endometrial cancer accounts for approximately 80 – 90% of all endometrial cancer cases and are often associated with the risk factors of obesity or increased estrogen exposure [ 16 , 17 ]. These tumors are often diagnosed at early stages and therefore have good prognoses [ 3 ]. Type II endometrial cancer commonly has mutations in the tumor promoter 53 ( TP53 ) oncogene in approximately 90% of cases. Type II endometrial cancer also accounts for approximately 75% of all endometrial cancer deaths and is more commonly diagnosed in Black women, therefore contributing to the inequity in mortality rates [ 3 , 17 , 18 ]. This review article will highlight recent advances in the knowledge of endometrial cancer, particularly a race conscious approach to diagnosis and treatment using nanoparticles. First, we discuss cross-cultural incidence rates of endometrial cancer followed by pre-clinical nanoparticle approaches to treat disease. We also investigate racial disparities in co-morbidity factors and genetic diversity among existing endometrial cancer in vitro and in vivo models. Throughout the article, the authors highlight critical needs for generating equitable evaluation and treatment of endometrial cancer.