Author : Valerie N. Barton
Publisher :
ISBN 13 :
Total Pages : 105 pages
Book Rating : 4.:/5 (956 download)
Book Synopsis The Role of Androgen Receptor in Triple-negative Breast Cancer by : Valerie N. Barton
Download or read book The Role of Androgen Receptor in Triple-negative Breast Cancer written by Valerie N. Barton and published by . This book was released on 2016 with total page 105 pages. Available in PDF, EPUB and Kindle. Book excerpt: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that lacks estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) amplification. Thus, TNBC does not respond to traditional endocrine or HER2-targeted therapies, has a poor prognosis, and lacks effective targeted therapies. Some TNBC tumors express androgen receptor (AR) and may benefit from AR targeted therapies. However, the function of AR in TNBC and efficacy of new generation AR inhibitors are unknown. I hypothesized that AR supports proliferation, metastatic potential, and cancer stem-like cell (CSC) maintenance and that inhibition of AR will decrease tumor burden in preclinical models of breast cancer. My work demonstrates that AR exhibits nuclear expression in at least 22% of primary TNBC tumors. While AR is most abundant in the “luminal AR” (LAR) subtype, non-LAR molecular subtypes are also critically dependent on AR protein. Indeed, AR inhibition significantly reduces baseline proliferation, anchorage-independent growth, migration, and invasion and increases apoptosis in non-LAR molecular subtypes. In vivo, the AR antagonist Enzalutamide (Enza) significantly decreases viability of non-LAR xenografts. Furthermore, AR regulates amphiregulin, which partially rescues the effects of AR inhibition on proliferation, migration, and invasion. AR transcript, protein, and transcriptional activity increase in tumors cells in suspension culture compared to attached conditions suggesting that AR may also maintain CSCs. Indeed, AR inhibition decreases CSCs in vitro. In vivo, pre-treatment with Enza decreases the tumor-initiating capacity of TNBC cells in a limiting dilution assay. Breast CSCs are enriched following chemotherapy and may repopulate the tumor. Indeed, Enza significantly decreases tumor burden when administered during or after chemotherapy in vivo. In summary, AR supports proliferation, metastatic phenotypes, tumor initiating capacity and maintenance of CSCs. AR targeted therapies may represent the first effective targeted therapy for TNBC and greatly improve patient outcomes.