Triple-negative breast cancers do not benefit from the targeted therapies that have greatly improved the survival of patients with other subtypes of breast cancer. But recent work shows that while these cancers lack estrogen receptors, progesterone receptors, and aren't driven by the gene HER2, up to a third of these tumors express the androgen receptor - clinical trials are underway to inhibit the androgen receptor in these tumors in much the same way that the drug Tamoxifen inhibits estrogen receptor in estrogen-receptor-positive breast cancers. A new University of Colorado Cancer Center study being presented today at the Endocrine Society Annual Meeting shows that even triple negative breast cancers expressing very low levels of androgen receptor may benefit from this therapy.
"This line of work is starting to change our thinking about who and when - the timing and patient selection for anti-androgen receptor therapy in triple-negative breast cancer," says Valerie Barton, the study's first author and PhD candidate in the lab of CU Cancer Center investigator Jennifer Richer, PhD.
Triple negative breast cancers were recently divided into further subtypes including a subtype with high androgen receptor expression (Lehmann, JCI 2011). However, other subtypes also express the androgen receptor. How would these different subtypes respond to anti-androgen receptor therapy? To find out, Barton and colleagues treated cell lines with the drug enzalutamide and with shRNAs designed to knock down androgen receptor levels. Interestingly, the drug enzalutamide is in wide use for prostate cancer, which tends to be driven by and dependent on androgen receptor.
Results showed that not only does anti-androgen receptor therapy reduce the ability of androgen-receptor-expressing triple-negative breast cancers to proliferate, migrate and invade, but for these cells, androgen receptor seems essential to survival. When Barton and colleagues blocked androgen receptor in these cells, the cells died.
But it was not only the high androgen-receptor-expressing cells that were affected.
"The study showed that androgen receptor has important roles in other subtypes of triple negative breast cancer as well," Barton says.
Across multiple triple-negative breast cancer subtypes, inhibiting the androgen receptor greatly increased apoptosis (programmed cell death), inhibited growth and increased necrosis by 60 percent in animal models.
"We're still early in the study of androgen receptor in breast cancer and already scientists are divvying up the disease to say, for example, that only the high AR expressing subtype should be treated with anti-androgen receptor therapies," Barton says. "But what we show is that even triple negative breast cancers with lower androgen receptor expression critically depend 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."