Approximately 15% to 20% of invasive breast carcinomas are triple-negative breast cancer (TNBC). These cancers lack estrogen and progesterone receptors, and are not driven by the human epidermal growth factor receptor 2 (HER2) gene. TNBC has the lowest 5-year survival rate of invasive breast carcinomas because it is an aggressive type and there are no targeted therapies.
However, recent work has shown that up to a third of TNBC tumors express the androgen receptor. Clinical trials are underway with drugs to inhibit the androgen receptor in much the same way that tamoxifen inhibits the estrogen receptor in estrogen-receptor-positive breast cancers.
A study presented at the Endocrine Society Annual Meeting in Chicago, Illinois, showed that TNBC that expressed even low levels of the androgen receptor may be affected by androgen receptor antagonists.
“This line of work is starting to change our thinking about patient selection for anti-androgen receptor therapy in triple-negative breast cancer,” says Valerie Barton, PhD candidate in the laboratory of Jennifer Richer, PhD, of the University of Colorado, Aurora.
Recently, TNBC was divided into further subtypes, including a subtype with high androgen receptor expression. However, other subtypes also express the androgen receptor, and nothing is known about their response to anti-androgen receptor therapy.
Barton and colleagues treated cell lines with the drug enzalutamide and with shRNAs designed to decrease androgen receptor levels. Enzalutamide, an androgen receptor antagonist, is used to treat castration-resistant metastatic prostate cancer.
Anti-androgen receptor therapy reduced the ability of TNBC that express androgen receptors to proliferate, migrate, and invade. More importantly, androgen receptors seemed to be essential for the survival of the tumor cells. When Barton and colleagues blocked the androgen receptors in these cells, the cells died.
However, cells expressing high levels of androgen receptors were not the only cells that were affected. A variety of TNBC cell subtypes had increased apoptosis (programmed cell death) and decreased growth when the androgen receptor was inhibited. In animal models, inhibition of androgen receptors increased necrosis by 60%.
“The study showed that androgen receptors have important roles in other subtypes of triple negative breast cancer. We are still early in the study of androgen receptors in breast cancer. Even triple-negative breast cancers with low androgen receptor expression are dependent on the androgen receptor and may benefit from anti-androgen receptor therapy. Our results suggest that anti-androgen receptor therapy may benefit a larger percentage of triple negative breast cancers than previously thought.”