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

Abstract

Amyloid precursor protein (APP) is a transmembrane protein that is highly expressed in brain tissue. Recently, APP has been implicated in some human malignancies, and its regulation by androgens has also been demonstrated. Such findings suggest the importance of APP in hormone-dependent breast carcinoma, but APP has not yet been examined in breast carcinoma tissues. Therefore, in this study, we examined the biological and clinical significance of APP in breast carcinoma using immunohistochemistry and in vitro studies. APP immunoreactivity was detected in 57 out of 117 (49%) breast carcinoma tissues examined, and it was positively associated with androgen receptor (AR) expression. APP immunoreactivity was also significantly associated with Ki-67 LI and increased risk of recurrence in the estrogen receptor (ER)-positive cases, and was an independent prognostic factor in these patients. Subsequent in vitro experiments demonstrated that APP mRNA expression was significantly induced by biologically active androgen dihydrotestosterone in both a dose-dependent and a time-dependent manner in MCF-7 breast carcinoma cells, which was potently suppressed by an AR blocker hydroxyflutamide. Moreover, cell proliferation activity of MCF-7 and MDA-MB-231 cells was significantly associated with their APP expression level. These findings suggest that APP is an androgeninduced gene that promotes proliferation activity of breast carcinoma cells. Moreover, APP immunohistochemical status is considered a potent prognostic factor in ER-positive breast cancer patients. (Cancer Sci 2013; 104: 1532-1538 B reast carcinoma is known as a hormone-dependent neoplasm, and estrogens play crucial roles in the development and ⁄ or progression of breast carcinoma. In addition, androgen receptor (AR) is expressed in a great majority of breast carcinoma tissues (1,2) and bioactive androgen dihydrotestosterone (DHT) is locally produced in the carcinoma, (3) suggesting the importance of androgens in breast carcinoma. Androgens are in 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 functions of androgens, including exploration of the androgen-regulated genes, in breast carcinoma. Amyloid precursor protein (APP) is a type I transmembrane protein, processed by a-, b-and c-secretase. One of the processed APP products, b-amyloid, is a major component of amyloid plaque, which is frequently detected in the brain tissues with Alzheimer's disease.(8) APP is also expressed in various nonneural tissues, and it is suggested to be involved in the growth of these cells.(9) APP has been implicated in several human malignancies, including lung, colon, pancreas, parathyroid, thyroid and prostate carcinomas, (10)(11)(12)(13)(14)(15) and the soluble N-terminal ectodomain fragment (sAPP) is reported to be responsible for the pro-proliferative effects of APP on carcinoma cells. (16) In addition, Takayama et al. (15) report that APP is an andro...

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TACC2 (transforming acidic coiled‐coil protein 2) in breast carcinoma as a potent prognostic predictor associated with cell proliferation

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