Amyloid precursor protein in human breast cancer An androgen‐induced gene associated with cell proliferation

Amyloid precursor protein (APP) is a transmembrane protein thatis highly expressed in brain tissue. Recently, APP has been implicatedin some human malignancies, and its regulation by androgenshas also been demonstrated. Such findings suggest theimportance of APP in hormone-dependent breast carcinoma, butAPP has not yet been examined in breast carcinoma tissues.Therefore, in this study, we examined the biological and clinicalsignificance of APP in breast carcinoma using immunohistochemistryand in vitro studies. APP immunoreactivity was detected in57 out of 117 (49%) breast carcinoma tissues examined, and itwas positively associated with androgen receptor (AR) expression.APP immunoreactivity was also significantly associated withKi-67 LI and increased risk of recurrence in the estrogen receptor(ER)-positive cases, and was an independent prognostic factor inthese patients. Subsequent in vitro experiments demonstratedthat APP mRNA expression was significantly induced by biologicallyactive androgen dihydrotestosterone in both a dose-dependentand a time-dependent manner in MCF-7 breast carcinomacells, which was potently suppressed by an AR blocker hydroxyflutamide.Moreover, cell proliferation activity of MCF-7 andMDA-MB-231 cells was significantly associated with their APPexpression level. These findings suggest that APP is an androgeninducedgene that promotes proliferation activity of breastcarcinoma cells. Moreover, APP immunohistochemical status isconsidered a potent prognostic factor in ER-positive breast cancerpatients. (Cancer Sci 2013; 104: 1532–1538)Breast carcinoma is known as a hormone-dependent neoplasm,and estrogens play crucial roles in the developmentand ⁄ or progression of breast carcinoma. In addition, androgenreceptor (AR) is expressed in a great majority of breast carcinomatissues(1,2) and bioactive androgen dihydrotestosterone(DHT) is locally produced in the carcinoma,(3) suggesting theimportance of androgens in breast carcinoma. Androgens arein general considered to suppress breast carcinoma cell proliferation,(4,5) but some divergent findings have been reported.(6,7)Therefore, it is very important to examine molecular functionsof androgens, including exploration of the androgen-regulatedgenes, in breast carcinoma.Amyloid precursor protein (APP) is a type I transmembraneprotein, processed by a-, b- and c-secretase. One of the processedAPP products, b-amyloid, is a major component ofamyloid plaque, which is frequently detected in the brain tissueswith Alzheimer’s disease.(8) APP is also expressed in variousnonneural tissues, and it is suggested to be involved inthe growth of these cells.(9) APP has been implicated inseveral human malignancies, including lung, colon, pancreas,parathyroid, thyroid and prostate carcinomas,(10–15) and thesoluble N-terminal ectodomain fragment (sAPP) is reported tobe responsible for the pro-proliferative effects of APP on carcinomacells.(16) In addition, Takayama et al.(15) report thatAPP is an androgen-induced gene in prostate carcinoma andfunctions as an important mediator of the androgen actions.These findings suggest possible roles of APP in human breastcarcinoma associated with androgen actions and ⁄ or cell proliferation.However, details of APP have not yet been studied inbreast carcinoma, and its significance has remained largelyunclear. Therefore, in the present study, we examine APP inbreast carcinoma using immunohistochemistry and in vitrostudies