Antiproliferative Effect of Androgen Receptor Inhibition in Mesenchymal Stem-Like Triple-Negative Breast Cancer

Abstract

Background/Aims: Androgen receptor (AR), a steroid hormone receptor, has recently emerged as prognostic and treatment-predictive marker in breast cancer. Previous studies have shown that AR is widely expressed in up to one-third of triple-negative breast cancer (TNBC). However, the role of AR in TNBC is still not fully understood, especially in mesenchymal stem-like (MSL) TNBC cells. Methods: MSL TNBC MDA-MB-231 and Hs578T breast cancer cells were exposed to various concentration of agonist 5-α-dihydrotestosterone (DHT) or nonsteroidal antagonist bicalutamide or untreated. The effects of AR on cell viability and apoptosis were determined by MTT assay, cell counting, flow cytometry analysis and protein expression of p53, p73, p21 and Cyclin D1 were analyzed by western blotting. The bindings of AR to p73 and p21 promoter were detected by ChIP assay. MDA-MB-231 cells were transplanted into nude mice and the tumor growth curves were determined and expression of AR, p73 and p21 were detected by Immunohistochemistry (IHC) staining after treatment of DHT or bicalutamide. Results: We demonstrate that AR agonist DHT induces MSL TNBC breast cancer cells proliferation and inhibits apoptosis in vitro. Similarly, activated AR significantly increases viability of MDA-MB-231 xenografts in vivo. On the contrary, AR antagonist, bicalutamide, causes apoptosis and exerts inhibitory effects on the growth of breast cancer. Moreover, DHT-dependent activation of AR involves regulation in the cell cycle related genes, including p73, p21 and Cyclin D1. Further investigations indicate the modulation of AR on p73 and p21 mediated by direct binding of AR to their promoters, and DHT could make these binding more effectively. Conclusions: Our study demonstrates the tumorigenesis role of AR and the inhibitory effect of bicalutamide in AR-positive MSL TNBC both in vitro and in vivo, suggesting that AR inhibition could be a potential therapeutic approach for AR-positive TNBC patients.

The Androgen Receptor Promotes Cellular Proliferation by Suppression of G-Protein Coupled Estrogen Receptor Signaling in Triple-Negative Breast Cancer

“…In line with our published data, which demonstrated that AR inhibitor exhibits antiproliferative effect in mesenchymal stem-like (MSL) TNBC cells [22], we observed the positive effect of DHT, a well-known AR agonist, on cellular viability of two AR-positive MSL TNBC cells, namely MDA-MB-231 and Hs578T. We assessed the positive action of increasing concentrations of DHT at 0.1 to 100 n M on MDA-MB-231 and Hs578T cells by MTT assay.…”

“…Our previous studies have revealed that DHT treatment significantly accelerated the in vivo growth of MDA-MB-231 xenograft tumors in comparison with the control treatment [22]. In the present study, to assess the effects of DHT treatment on AR and GPER levels in the primary tumor xenografts, IHC staining analysis was conducted on the harvested xenogrft tumors obtained from our previous experiment as mentioned.…”

High Expression of CCR7 Predicts Lymph Node Metastasis and Good Prognosis in Triple Negative Breast Cancer

“…Such roles have been extensively studied in adaptive immunity and secondary lymphoid organogenesis [13, 14]. The CCR7 -null mice mutant displayed a disrupted architecture of the thymus and lymph nodes, as well as reduced primary immune response [9].…”

MiR-212-5p Suppresses the Epithelial-Mesenchymal Transition in Triple-Negative Breast Cancer by Targeting Prrx2

“…Understanding the molecular mechanisms that regulate the EMT process is crucial for improving breast carcinoma treatment [22, 23]. Our study showed that ectopic expression of miR-212-5p in TNBC cells impaired their invasion, proliferation and growth.…”