Title

5α-dihydrotestosterone down-regulates HER2 and sensitizes breast cancer cells to Herceptin-induced apoptosis in vitro

Document Type

Article

Department

Pathology and Laboratory Medicine

Abstract

Androgen inhibits growth of malignant breast cancer (BCa) cells by mechanisms that remain poorly defined. Here, we have investigated how androgen suppress proliferation and induces apoptosis in BCa cells. Treatment of MCF-7 cells with 1nM 5α-dihydrotestosterone (DHT) inhibited cell proliferation as well as endogenous HER2 expression, both at mRNA and protein levels, suggesting a link between androgen receptor (AR) and HER2 signaling pathways. Expression of HER2 and AR was also determined in patients with BCa. We found a survival advantage of AR expression in patients with HER2 positive BCa, whereas, loss of AR expression was associated with poor survival. This finding would suggest that AR loss may provide a growth advantage to HER2 over-expressing tumors. We showed the functional consequence of the stimulation of AR-signaling and inhibition of HER2-signaling on breast epithelial cell growth and on expression of 84 genes involved in BCa and estrogen-mediated signaling pathway. Exposure to a combination therapy of DHT and Herceptin resulted in additive anti-proliferative effect in human MCF-7 cells as compared to either agent alone. Furthermore, combined treatment of DHT with Herceptin reduces the expression of genes predominantly involved in proliferation, invasion, anti-apoptosis and cell cycle regulation.
These findings provide the key insights into how Herceptin and DHT produce anti-proliferative effect in BCa cells. In conclusion, adding DHT to Herceptin may provide a rational treatment option for BCa, not only by direct inhibition of cell proliferation, but also causing changes in the expression of many genes that are critically involved in the control of proliferation. Establishment of any interaction between AR and HER2 may improve the understanding of carcinogenesis and will provide helpful information in the development of novel preventive and therapeutic strategies.

Publication

Cancer Research