Cabergoline Prevents Postpartum Breast Cancer by Enhancing Mammary Gland Involution in Brca1-Mutant Mice and Reduces Risk in Younger Women

Cabergoline Prevents Postpartum Breast Cancer by Enhancing Mammary Gland Involution in Brca1-Mutant Mice and Reduces Risk in Younger Women | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Cabergoline Prevents Postpartum Breast Cancer by Enhancing Mammary Gland Involution in Brca1 -Mutant Mice and Reduces Risk in Younger Women Natalia García-Sancha, Roberto Corchado-Cobos, Ryan Ghorayeb, and 37 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3854490/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Breast cancer that arises in the postpartum period often carries a poor prognosis. The increasing trend of later-life pregnancies further exacerbates this risk. We urgently need chemoprevention strategies that reduce risk for postpartum period tumors, especially for more-aggressive ER-negative tumors and for those that arise in women with a genetic susceptibility. Here, we report that a single post-lactation dose of cabergoline, a dopaminergic agonist that blocks prolactin secretion, delays the onset and reduces the incidence of mammary cancer that arises postpartum in K14-Cre; Brca1 F/F , Trp53 F/F mice. In these mice, cabergoline treatment remodels the postpartum mammary gland by potentiating involution, reducing ductal area and proliferation, and reversing T cell exhaustion, potentially through modulation of ion channel expression. Notably, independent retrospective studies in two large cohorts of European women demonstrated a markedly lower incidence of postpartum breast cancer in those treated with cabergoline compared to a control group, with a meta-analysis indicating an approximate 69% reduction in risk. Our work underscores the importance of targeting post-lactational involution as a strategy for the prevention of postpartum breast cancer and identifies cabergoline as a novel, low-risk chemoprevention strategy during the vulnerable postpartum window by promoting physiological remodeling and mitigating immune dysfunction. Health sciences/Diseases/Cancer/Cancer prevention Biological sciences/Cancer/Breast cancer Health sciences/Medical research/Translational research Health sciences/Health care/Disease prevention/Preventive medicine Cabergoline Breast Cancer Prevention Postpartum Breast Cancer Brca1-Mutant Mice Post-lactational Involution Mammary Gland Remodeling Binucleated Alveolar Cells T Cell exhaustion Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Full Text Additional Declarations The authors declare no competing interests. Supplementary Files SupplementaryFigures.pdf Supplementary Figures SupplementaryTables.xlsx Supplementary Tables Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3854490","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":271158869,"identity":"67dd08a4-a143-4d53-80bf-e353f9b96039","order_by":0,"name":"Natalia García-Sancha","email":"","orcid":"","institution":"1 Centro de Investigación del Cáncer (CIC), Universidad de Salamanca/CSIC, Salamanca, España. 2 Instituto de Investigación Biosanitaria de Salamanca (IBSAL), Salamanca, España.","correspondingAuthor":false,"prefix":"","firstName":"Natalia","middleName":"","lastName":"García-Sancha","suffix":""},{"id":271158870,"identity":"583352dd-a415-49b2-949f-60a91f54a70f","order_by":1,"name":"Roberto Corchado-Cobos","email":"","orcid":"","institution":"1 Centro de Investigación del Cáncer (CIC), Universidad de Salamanca/CSIC, Salamanca, España. 2 Instituto de Investigación Biosanitaria de Salamanca (IBSAL), Salamanca, España.","correspondingAuthor":false,"prefix":"","firstName":"Roberto","middleName":"","lastName":"Corchado-Cobos","suffix":""},{"id":579532332,"identity":"b35d14c6-9741-4bc0-9629-61289f0bd5ae","order_by":2,"name":"Ryan Ghorayeb","email":"","orcid":"","institution":"(3) Department of Pediatrics, University of British Columbia, Vancouver, Canada.","correspondingAuthor":false,"prefix":"","firstName":"Ryan","middleName":"","lastName":"Ghorayeb","suffix":""},{"id":271158871,"identity":"446397bf-d3a7-401b-9ff2-f1cbdbe2560f","order_by":3,"name":"Adrián Blanco-Gómez","email":"","orcid":"","institution":"(1) Centro de Investigación del Cáncer (CIC), Universidad de Salamanca/CSIC, Salamanca, España. 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(2) Instituto de Investigación Biosanitaria de Salamanca (IBSAL), Salamanca, España.","correspondingAuthor":true,"prefix":"","firstName":"Jesús","middleName":"","lastName":"Pérez-Losada","suffix":""}],"badges":[],"createdAt":"2024-01-11 19:05:08","currentVersionCode":2,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-3854490/v2","doiUrl":"https://doi.org/10.21203/rs.3.rs-3854490/v2","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":101150573,"identity":"d39d2d6c-4cb8-4f7f-8319-9e90d31ddd67","added_by":"auto","created_at":"2026-01-26 15:42:10","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":150332,"visible":true,"origin":"","legend":"\u003cp\u003ePostpartum treatment with cabergoline reduces mammary tumor incidence\u003c/p\u003e\n\u003cp\u003eand increases latency in K14-Cre, BP mutant mice. a) The study design included three\u003c/p\u003e\n\u003cp\u003ecohorts: nulliparous mice (N=35), nursing mice that completed two pregnancies with\u003c/p\u003e\n\u003cp\u003elactation (nursing group, N=32), and nursing mice treated with cabergoline post-lactation\u003c/p\u003e\n\u003cp\u003e(cabergoline group, N=37). The nursing mice were mated at 6 weeks of age and\u003c/p\u003e\n\u003cp\u003eunderwent two cycles of pregnancy and weaning. Each lactation period lasted for 21 days.\u003c/p\u003e\n\u003cp\u003eCabergoline treatment was administered on the day of the second weaning when the mice\u003c/p\u003e\n\u003cp\u003ewere aged 120–130 days. b, c) Tumor latency (days from birth to first palpable tumor)\u003c/p\u003e\n\u003cp\u003e(b) and incidence (c) comparisons between nulliparous and nursing mice, with and\u003c/p\u003e\n\u003cp\u003ewithout cabergoline treatment. d) Additional experimental group: nulliparous mice\u003c/p\u003e\n\u003cp\u003ereceiving a single cabergoline dose (aged 120 – 130 days). e, f) Analysis of tumor latency\u003c/p\u003e\n\u003cp\u003e(e) and incidence (f) in nulliparous mice treated with cabergoline (N=37). Tumor latency\u003c/p\u003e\n\u003cp\u003eand incidence were assessed using Kaplan-Meier survival curves (b, e) and Chi-square\u003c/p\u003e\n\u003cp\u003etests (c, f), respectively. The Kaplan-Meier graphs illustrate the timing of mammary\u003c/p\u003e\n\u003cp\u003etumor appearance, measuring latency from birth to tumor detection. The incidence data\u003c/p\u003e\n\u003cp\u003erepresent the cumulative tumor occurrence throughout the entire lifespan of the animals,\u003c/p\u003e\n\u003cp\u003efrom birth until euthanasia, due to tumor development or general health decline.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3854490/v2/ea4408d74d3cf38bfaf49776.png"},{"id":101150041,"identity":"45a809b2-172c-4e43-a65b-13854ce3a2dc","added_by":"auto","created_at":"2026-01-26 15:40:37","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":850815,"visible":true,"origin":"","legend":"\u003cp\u003ePostpartum treatment with cabergoline is associated with changes in\u003c/p\u003e\n\u003cp\u003epremalignant mammary gland structures and proliferation as associative risk\u003c/p\u003e\n\u003cp\u003esurrogates in K14-Cre, BP mutant mice. a) Histological images for the analysis of the\u003c/p\u003e\n\u003cp\u003eductal area in mammary tissues isolated in the cross-sectional cohort (at 60 days post-\u003c/p\u003e\n\u003cp\u003eweaning). b) Ductal area assessment at 60 days post-weaning (age: 160-170 days) in\u003c/p\u003e\n\u003cp\u003enursing mice, untreated and treated with cabergoline, and age-matched nulliparous mice (five-six mice per group). c) Histological images displaying Ki-67 staining at 60 days\u003c/p\u003e\n\u003cp\u003epost-weaning (four to five mice per group). d) Ki-67 proliferation analysis at 60 days\u003c/p\u003e\n\u003cp\u003epost-weaning. e) Enrichment analysis of downregulated differentially expressed genes in\u003c/p\u003e\n\u003cp\u003ethe longitudinal cohort of non-cancerous mammary glands isolated at humane endpoint\u003c/p\u003e\n\u003cp\u003efrom cabergoline-treated nursing K14-Cre, BP mutant mice (N=7) compared to untreated\u003c/p\u003e\n\u003cp\u003econtrols (N=6), highlighting processes related to glandular development, inflammation,\u003c/p\u003e\n\u003cp\u003eand immune responses. See Supplementary Table 1.1 for details b and d. The error bars\u003c/p\u003e\n\u003cp\u003erepresent the SEM, with the mean indicating central tendency. Statistical significance\u003c/p\u003e\n\u003cp\u003edetermined by Kruskal-Wallis test with Dunn’s post-hoc test; *P \u0026lt; 0.05, **P \u0026lt; 0.01, ***P\u003c/p\u003e\n\u003cp\u003e\u0026lt; 0.001.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3854490/v2/ebc7a367e42e6991a935decc.png"},{"id":101150095,"identity":"8b80a46b-e5c7-4dfa-9e5a-9464880ef015","added_by":"auto","created_at":"2026-01-26 15:40:50","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":460373,"visible":true,"origin":"","legend":"\u003cp\u003eCabergoline treatment is associated with recombinant cell dynamics and a\u003c/p\u003e\n\u003cp\u003ereduction in epithelial subpopulations in K14-Cre, BP mutant mice. a) Quantitative\u003c/p\u003e\n\u003cp\u003ePCR analysis: measures the recombinant quantity (RQ) of the Trp53 allele (P53) in\u003c/p\u003e\n\u003cp\u003evarious mouse groups of the longitudinal cohort to assess the association with cabergoline\u003c/p\u003e\n\u003cp\u003etreatment. b-d) Correlation studies: investigate the relationship between recombinant\u003c/p\u003e\n\u003cp\u003eTrp53 allele quantity and age of mice in different cohorts; a-d, 11 mice per group were\u003c/p\u003e\n\u003cp\u003eevaluated. e) Comparative analysis: cross-sectional comparison of the Trp53 allele across\u003c/p\u003e\n\u003cp\u003emouse groups. f) Recombinant cell quantification adjusts the number of recombinant cells\u003c/p\u003e\n\u003cp\u003efor ductal area differences; e, f, five mice per group were assessed. g) RFP+ recombinant\u003c/p\u003e\n\u003cp\u003emouse model: describes the methodology for generating RFP+ recombinant K14-Cre, BP\u003c/p\u003e\n\u003cp\u003emutant mice. h) RFP detection: immunohistochemical analysis of RFP-positive cells in\u003c/p\u003e\n\u003cp\u003emammary glands of various groups. i) Flow cytometry analysis: quantifies RFP+ cells in\u003c/p\u003e\n\u003cp\u003eK14-Cre, BP mutant mice. j) measurement: examines ductal area in the context of\u003c/p\u003e\n\u003cp\u003ecabergoline area treatment in RFP+ mice. k) Absolute RFP+ cell count: adjusts the number of RFP+ cells for ductal area (d.a.). l) Subpopulation assessments: flow cytometry\u003c/p\u003e\n\u003cp\u003estudy of the associations with cabergoline on recombinant breast epithelial\u003c/p\u003e\n\u003cp\u003esubpopulations. m, n) Epithelial subpopulation examination: analyzes specific RFP+\u003c/p\u003e\n\u003cp\u003eepithelial subpopulations (m), with corrections for ductal area (d.a.) differences (n) in\u003c/p\u003e\n\u003cp\u003eluminal and basal cells. i-n, nulliparous (N = 9), nursing (N = 11), and cabergoline-treated\u003c/p\u003e\n\u003cp\u003e(N =8) mice. Statistical analysis includes the Kruskal-Wallis test and the Wilcoxon post-\u003c/p\u003e\n\u003cp\u003etest (Panels a, e, f, i, j, k, m, n) and the Spearman test (Panels b-d). Significance denoted\u003c/p\u003e\n\u003cp\u003eas *** P \u0026lt; 0.0005; ** P \u0026lt; 0.005; * P \u0026lt; 0.05. Panels a, e, f, j: Error bars indicate SEM,\u003c/p\u003e\n\u003cp\u003ewith the mean showing central tendency. Panels i, k, m, n: Box plots display the median\u003c/p\u003e\n\u003cp\u003eand interquartile range\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-3854490/v2/2678453a15817e29698b3def.png"},{"id":101150018,"identity":"3594e01c-383e-4473-87a6-ff436d580ee1","added_by":"auto","created_at":"2026-01-26 15:40:31","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":2005900,"visible":true,"origin":"","legend":"\u003cp\u003ePost-lactational involution is delayed in the mammary glands of BP mutant\u003c/p\u003e\n\u003cp\u003emice, and can be augmented by cabergoline treatment. a, b) Immunofluorescence\u003c/p\u003e\n\u003cp\u003eanalysis of day 3 involution glands stained with EpCAM (red) and Hoechst (blue)\u003c/p\u003e\n\u003cp\u003ecomparing epithelial area in cabergoline-treated and untreated mice from both wildtype\u003c/p\u003e\n\u003cp\u003e(WT) and K14-Cre, BP mutant genotypes. Scale bars are 200 microns. c, d)\u003c/p\u003e\n\u003cp\u003eImmunofluorescence analysis of day 3 involution glands stained with EpCAM (red) and\u003c/p\u003e\n\u003cp\u003eHoechst (blue) comparing binucleate cells in cabergoline-treated and untreated mice from\u003c/p\u003e\n\u003cp\u003eboth WT and K14-Cre, BP mutant genotypes. Binucleate cells are shown in boxes. Scale\u003c/p\u003e\n\u003cp\u003ebars are 20 microns. e, f) Histopathological examination of mammary gland adipocyte\u003c/p\u003e\n\u003cp\u003eexpansion at 1-, 3-, and 7-days post-lactation, comparing cabergoline-treated and\u003c/p\u003e\n\u003cp\u003euntreated mice from both WT and K14-Cre, BP mutant genotypes. g, h) Apoptosis\u003c/p\u003e\n\u003cp\u003eanalysis using cleaved-caspase 3 staining at corresponding timepoints; a-h, 4-5 mice per\u003c/p\u003e\n\u003cp\u003egroup were evaluated, each data point represents one region of interest. i, j) Assessment\u003c/p\u003e\n\u003cp\u003eof pSTAT3 and pSTAT5 protein levels in epithelial-enriched tissue fragments on day 3 post-treatment of five mice per group. The ratio of pSTAT3/5 to STAT3/5 was measured,\u003c/p\u003e\n\u003cp\u003eas well as the ratio of pSTAT3/5 to total protein. One-way ANOVA (Tukey’s multiple\u003c/p\u003e\n\u003cp\u003ecomparisons) was used to calculate p values for panels b and d, and Mann-Whitney U\u003c/p\u003e\n\u003cp\u003etests were used to calculate p values for panels f, h, and j. Panels b-h, lines in box plots\u003c/p\u003e\n\u003cp\u003erepresent the median, and error bars represent the minimum and maximum values. Panel\u003c/p\u003e\n\u003cp\u003ej, the median indicates central tendency, and error bars show the interquartile range.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-3854490/v2/485b4b464930a187fd65093e.png"},{"id":101150197,"identity":"fe7d58a2-918f-44f3-83c8-e6cf1a4eb769","added_by":"auto","created_at":"2026-01-26 15:41:00","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1684472,"visible":true,"origin":"","legend":"\u003cp\u003eT cell infiltration is increased, with frequent expression of an exhausted\u003c/p\u003e\n\u003cp\u003ephenotype, in mammary tissue isolated at day 4 involution from Blg-Cre, BP mutant\u003c/p\u003e\n\u003cp\u003emice. a) Cartoon schematic depicting mouse samples used for scRNA seq and\u003c/p\u003e\n\u003cp\u003eimmunofluorescence. b) Tissue sections from Blg-Cre BP mutant and control (CTL)\u003c/p\u003e\n\u003cp\u003egenotype mice, stained for EpCAM+ positive cells. Whole tissue sections were quantified\u003c/p\u003e\n\u003cp\u003efrom four mice per group, and an unpaired t-test was used to determine the p-value. Scale\u003c/p\u003e\n\u003cp\u003ebars are 2 mm in large images and 200 microns in regions of interest. c) UMAP of scRNA\u003c/p\u003e\n\u003cp\u003eseq dataset post quality control. Clusters were annotated based on lineage, and the\u003c/p\u003e\n\u003cp\u003eproportion of lineage is quantified in bar graphs below. d) Beeswarm plot of MILO DA\u003c/p\u003e\n\u003cp\u003eresults. Dots highlighted in red have a spatial FDR value of less than 0.2 (p\u0026lt;0.01).\u003c/p\u003e\n\u003cp\u003ePositive log fold changes are neighborhoods enriched with Blg-Cre, BP mutant (BP) cells,\u003c/p\u003e\n\u003cp\u003ewhile negative values are neighborhoods enriched with Brca1F/F, no Cre (CTL), and\u003c/p\u003e\n\u003cp\u003eTrp53+/- (P53) cells. e) Chord plots from receptor-ligand analyses. Chord plots were\u003c/p\u003e\n\u003cp\u003egenerated for each of the 4 interactions that were only present in the BP mutant samples\u003c/p\u003e\n\u003cp\u003eand immunomodulatory. Arrowheads point to clusters where cells are expressing the\u003c/p\u003e\n\u003cp\u003ereceptor, while the opposite ends of lines point to clusters where cells are expressing\u003c/p\u003e\n\u003cp\u003eligands. f) Broad immune cell, g) macrophage, and h) T cell-specific multiplex\u003c/p\u003e\n\u003cp\u003eimmunofluorescence panels and quantification of the various immune populations per unit area. Each data point represents one region of interest (n=2 mice per genotype, except\u003c/p\u003e\n\u003cp\u003efor CD8 and F/480, n=4 mice per genotype), and populations with significant p values\u003c/p\u003e\n\u003cp\u003e(\u0026lt;0.05) are highlighted in red. Scale bars are 100 microns. f-h, p-values were calculated\u003c/p\u003e\n\u003cp\u003eby Mann-Whitney U tests.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-3854490/v2/700cd41c5a76fdf1b57af71d.png"},{"id":101150190,"identity":"55a7f9c5-fddc-4646-b712-31f5d179381b","added_by":"auto","created_at":"2026-01-26 15:40:55","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":1653186,"visible":true,"origin":"","legend":"\u003cp\u003eCabergoline treatment modulates expression of ion transporters and modifies\u003c/p\u003e\n\u003cp\u003ethe T cell phenotype during involution in K14-Cre, BP mutant mice. a) Pre-ranked\u003c/p\u003e\n\u003cp\u003eGSEA analysis and associated heatmaps displaying the normalized enrichment scores\u003c/p\u003e\n\u003cp\u003e(NES) for the significant associations between Hallmark gene sets and mammary tissue\u003c/p\u003e\n\u003cp\u003e24 hours post-cabergoline treatment. Asterisks indicate statistically significant\u003c/p\u003e\n\u003cp\u003eassociations (see inset for thresholds). Negative enrichment indicates lower scores in the\u003c/p\u003e\n\u003cp\u003ecabergoline-treated samples compared to untreated control samples (RNA-seq; N=5\u003c/p\u003e\n\u003cp\u003econtrols, N=4 treated). See Supplementary Table 2.2 for details. b) GSEA plots for\u003c/p\u003e\n\u003cp\u003eselected hallmark gene sets from panel a. c) Pre-ranked GSEA analysis and associated\u003c/p\u003e\n\u003cp\u003eheatmaps displaying the normalized enrichment scores (NES) for the significant\u003c/p\u003e\n\u003cp\u003eassociations between GO molecular function gene sets and mammary tissue 24 hours\u003c/p\u003e\n\u003cp\u003epost-cabergoline treatment. See Supplementary Table 2.3 for details. d) GSEA plots for\u003c/p\u003e\n\u003cp\u003eselected gene sets from panel c relating to ion transport. e, f) Immunofluorescence images\u003c/p\u003e\n\u003cp\u003eand quantification (see Supplementary Fig. 14) of ATP1A2 in tissue sections from K14-\u003c/p\u003e\n\u003cp\u003eCre, BP mutant mice with and without cabergoline at day one involution. Scale bars are\u003c/p\u003e\n\u003cp\u003e50 microns. Data points represent regions analyzed (n=4 mice per group). g)\u003c/p\u003e\n\u003cp\u003eImmunofluorescence images of cytotoxic T cells in tissue sections from K14-Cre, BP\u003c/p\u003e\n\u003cp\u003emutant mice with and without cabergoline at day one involution. Scale bars are 100\u003c/p\u003e\n\u003cp\u003emicrons in large images, and 5 microns in smaller regions of interest. Quantification of\u003c/p\u003e\n\u003cp\u003eg) Total cytotoxic T cell per unit area, and h) Percent of cytotoxic T cells that were Tox2 positive. Data points represent regions analyzed (n=4 mice per group). f-i, p-values were\u003c/p\u003e\n\u003cp\u003ecalculated via Mann-Whitney U tests.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-3854490/v2/2e3be213904f8bd6f339bf77.png"},{"id":101150039,"identity":"32463545-4cef-470e-b821-b958e1df900e","added_by":"auto","created_at":"2026-01-26 15:40:37","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":181602,"visible":true,"origin":"","legend":"\u003cp\u003eAssociation between postpartum treatment with cabergoline and a reduced\u003c/p\u003e\n\u003cp\u003erisk of early-onset breast cancer in women. a) Cumulative incidence in older first-time\u003c/p\u003e\n\u003cp\u003emothers: analyzes the cumulative incidence of breast cancer in women who had their first\u003c/p\u003e\n\u003cp\u003echild at age 30 or older, comparing those who received cabergoline postpartum with\u003c/p\u003e\n\u003cp\u003econtrols. b) Multivariate Cox regression in older first-time mothers: assesses the influence\u003c/p\u003e\n\u003cp\u003eof cabergoline intake and other variables on breast cancer risk using a multivariate Cox\u003c/p\u003e\n\u003cp\u003eregression model. c) Cumulative incidence in a decade post-first pregnancy: shows the\u003c/p\u003e\n\u003cp\u003ecumulative incidence of breast cancer within ten years following the first pregnancy in a\u003c/p\u003e\n\u003cp\u003ebroader cohort. d) Multivariate Cox regression analysis in a decade post-first pregnancy:\u003c/p\u003e\n\u003cp\u003eexamines breast cancer risk factors post-first partum, including cabergoline intake,\u003c/p\u003e\n\u003cp\u003ethrough multivariate Cox regression analysis. e) Cumulative breast cancer incidence in\u003c/p\u003e\n\u003cp\u003ewomen who used cabergoline from the Norway dataset with fully adjusted hazard ratios.\u003c/p\u003e\n\u003cp\u003ef) Forest plot of breast cancer incidence in women who received cabergoline in the\u003c/p\u003e\n\u003cp\u003eSIDIAP dataset, the Norway dataset, and pooled analysis.\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-3854490/v2/e502cd03d2eba68fb1321a8e.png"},{"id":101206257,"identity":"3c9a3e1a-f095-44ff-a369-81baa5e3f544","added_by":"auto","created_at":"2026-01-27 09:55:48","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2691396,"visible":true,"origin":"","legend":"","description":"","filename":"ManuscriptmaintextV2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3854490/v2_covered_814203f9-35bc-4f14-9f48-c9b95f1cb81f.pdf"},{"id":101150341,"identity":"b2da3cb2-52dd-46a6-b9ec-c8de7ffccb13","added_by":"auto","created_at":"2026-01-26 15:41:18","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":83104403,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Figures\u003c/p\u003e","description":"","filename":"SupplementaryFigures.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3854490/v2/38ecec8276f8206790f3402a.pdf"},{"id":101150229,"identity":"49dca3fd-3b64-4025-826b-55dca04d5d4b","added_by":"auto","created_at":"2026-01-26 15:41:06","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":403476,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Tables\u003c/p\u003e","description":"","filename":"SupplementaryTables.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3854490/v2/f2f8fbca6fdca64624231102.xlsx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eCabergoline Prevents Postpartum Breast Cancer by Enhancing Mammary Gland Involution in \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eBrca1\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e-Mutant Mice and Reduces Risk in Younger Women\u003c/strong\u003e\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":" Cabergoline, Breast Cancer Prevention, Postpartum Breast Cancer, Brca1-Mutant Mice, Post-lactational Involution, Mammary Gland Remodeling, Binucleated Alveolar Cells, T Cell exhaustion","lastPublishedDoi":"10.21203/rs.3.rs-3854490/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3854490/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBreast cancer that arises in the postpartum period often carries a poor prognosis. The increasing trend of later-life pregnancies further exacerbates this risk. We urgently need chemoprevention strategies that reduce risk for postpartum period tumors, especially for more-aggressive ER-negative tumors and for those that arise in women with a genetic susceptibility. Here, we report that a single post-lactation dose of cabergoline, a dopaminergic agonist that blocks prolactin secretion, delays the onset and reduces the incidence of mammary cancer that arises postpartum in \u003cem\u003eK14-Cre;\u003c/em\u003e \u003cem\u003eBrca1\u003c/em\u003e\u003csup\u003eF/F\u003c/sup\u003e\u003cem\u003e, Trp53\u003c/em\u003e\u003csup\u003e\u003cem\u003eF/F\u003c/em\u003e\u003c/sup\u003e mice. In these mice, cabergoline treatment remodels the postpartum mammary gland by potentiating involution, reducing ductal area and proliferation, and reversing T cell exhaustion, potentially through modulation of ion channel expression. Notably, independent retrospective studies in two large cohorts of European women demonstrated a markedly lower incidence of postpartum breast cancer in those treated with cabergoline compared to a control group, with a meta-analysis indicating an approximate 69% reduction in risk. Our work underscores the importance of targeting post-lactational involution as a strategy for the prevention of postpartum breast cancer and identifies cabergoline as a novel, low-risk chemoprevention strategy during the vulnerable postpartum window by promoting physiological remodeling and mitigating immune dysfunction.\u003c/p\u003e","manuscriptTitle":"Cabergoline Prevents Postpartum Breast Cancer by Enhancing Mammary Gland Involution in Brca1-Mutant Mice and Reduces Risk in Younger Women","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2026-01-26 15:38:55","doi":"10.21203/rs.3.rs-3854490/v2","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2024-02-05 15:15:51","doi":"10.21203/rs.3.rs-3854490/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"771bddbf-2820-465c-b874-985978912cc3","owner":[],"postedDate":"January 26th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":61661745,"name":"Health sciences/Diseases/Cancer/Cancer prevention"},{"id":61661746,"name":"Biological sciences/Cancer/Breast cancer"},{"id":61661747,"name":"Health sciences/Medical research/Translational research"},{"id":61661748,"name":"Health sciences/Health care/Disease prevention/Preventive medicine"}],"tags":[],"updatedAt":"2026-01-22T16:04:09+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-26 15:38:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-3854490","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3854490","identity":"rs-3854490","version":["v2"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}