Androgens are hormones, such as testosterone, that are important for normal male sexual development before birth and during puberty. Androgen receptors allow the body to respond appropriately to these hormones. In normal breast development, estrogen stimulates, and androgen inhibits, growth at puberty and throughout adult life. Abnormal estrogen activity is responsible for the majority of breast cancers, but the role of androgen activity in this disease has been controversial. However, researchers at the University of Adelaide have found new evidence about the positive role of androgens in breast cancer treatment with immediate implications for women with estrogen receptor-driven metastatic disease.

Their findings were recently published in Nature Medicine in a paper titled, “The androgen receptor is a tumor suppressor in estrogen receptor-positive breast cancer.”

There have been previous studies that suggest that androgens normally inhibit mammary epithelial proliferation and breast growth. The role that androgens play in breast cancer has been controversial.

“The role of the androgen receptor (AR) in estrogen receptor (ER)-α-positive breast cancer is controversial, constraining implementation of AR-directed therapies,” the researchers wrote. “Using a diverse, clinically relevant panel of cell-line and patient-derived models, we demonstrate that AR activation, not suppression, exerts potent antitumor activity in multiple disease contexts, including resistance to standard-of-care ER and CDK4/6 inhibitors. Notably, AR agonists combined with standard-of-care agents enhanced therapeutic responses.”

Androgens were historically used to treat breast cancer, but knowledge of hormone receptors in the treatment’s efficacy was misunderstood. Androgen therapy was discontinued due to side effects and the rise of anti-estrogenic endocrine therapies.

While endocrine therapy is standard-of-care for estrogen receptor-positive breast cancer, resistance to these drugs is the major cause of breast cancer mortality. The researchers saw a need for an alternative treatment to overcome resistance and focused their attention on androgen therapy.

Using cell-line and patient-derived models, the international team of researchers from the University of Adelaide and the Garvan Institute, showed that androgen receptor activation by natural androgen or a new androgenic drug had potent anti-tumor activity in all estrogen receptor-positive breast cancers, even those resistant.

“This work has immediate implications for women with metastatic estrogen receptor-positive breast cancer, including those resistant to current forms of endocrine therapy,” explained Theresa Hickey, PhD, associate professor, University of Adelaide.

“The new insights from this study should clarify the widespread confusion over the role of the androgen receptor in estrogen receptor driven breast cancer,” stated associate professor Elgene Lim, PhD, a breast oncologist and head of the Connie Johnson Breast Cancer Research Lab at the Garvan Institute. “Given the efficacy of this treatment strategy at multiple stages of disease in our study, we hope to translate these findings into clinical trials as a new class of endocrine therapy for breast cancer.”

“These findings provide unambiguous evidence that AR has a tumor suppressor role in ER-positive breast cancer and support AR agonism as the optimal AR-directed treatment strategy, revealing a rational therapeutic opportunity,” concluded the researchers.