Among
breast cancer types,
triple-negative breast cancer (TNBC) has the fewest treatment options and the lowest 5-year survival rate.
Androgen receptor (AR) inhibition has displayed efficacy against
breast cancer preclinically and is currently being examined clinically in AR positive TNBC patients.
Androgen deprivation has been shown to induce immunogenic modulation; the alteration of
tumor cell phenotype resulting in increased sensitivity to immune-mediated killing. We evaluated the ability of AR inhibition to reduce the growth and improve the immune-mediated killing of
breast cancer cells with differing expression of the
estrogen receptor and AR. While AR expression was required for the growth inhibitory effects of
enzalutamide on
breast cancer cells, both
enzalutamide and
abiraterone improved the sensitivity of
breast cancer cells to immune-mediated lysis independent of detectable AR expression. This increase in sensitivity was linked to an increase in cell surface
tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL) receptor expression as well as a significant reduction in the expression of
osteoprotegerin (OPG). The reduction in OPG was further examined and found to be critical for the increase in sensitivity of AR- TNBC cells to immune-mediated killing. The data presented herein further support the use of AR inhibition
therapy in the AR+ TNBC setting. These data, however, also support the consideration of AR inhibition
therapy for the treatment of AR- TNBC, especially in combination with
cancer immunotherapy, providing a potential novel therapeutic option for select patients.