The role of estrogen in the development of certain breast cancers is well known, but a new study from researchers in Australia is shining renewed light on the role of another less commonly discussed hormone in breast cancer: androgen. In the study, Theresa E. Hickey, PhD, head of the Breast Cancer Group at the University of Adelaide, and colleagues provide evidence that the androgen receptor has tumor suppressor roles in estrogen receptor (ER)-positive breast cancer.1

“Early in breast cancer research, before we had a full understanding of these hormone receptors, it was thought that maybe we could treat women with androgen hormones that were produced in the clinic because they might oppose the action of estrogen,” Dr Hickey said. “Women were given these powerful androgen hormones. They were effective, but we had no idea why.”

In the past 30 years, many treatment approaches involved reducing estrogen levels, according to Matthew J. Ellis, MD, BChir, PhD, director of the Lester and Sue Smith Breast Center and Baylor College of Medicine. This is done surgically or with the use of aromatase inhibitors. “In the early 90s, we were still giving testosterone as a third- or fourth-line endocrine therapy for ER-positive breast cancer because we didn’t have mTOR inhibitors and CDK 4/6 inhibitors back then,” commented Dr Ellis. “We had more rudimentary therapy, so it was justifiable.”

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The problem, Dr Hickey and Dr Ellis explained, was that these testosterone or androgen treatments had virilizing effects. Male-pattern hair growth and other traditionally masculine physical traits developed in treated women. At the same time, ER antagonists, such as tamoxifen, were being developed and were found to effectively treat breast cancers without causing the virilization.

A New Role

“Androgen hormones were chucked out the window.” That is, until recently when Dr Hickey and Wayne Tilley, PhD, director of the Dame Roma Mitchel Cancer Research Laboratories at University of Adelaide, and colleagues began to look more closely at the androgen receptor in the setting of breast cancer tumors and examine ways to exploit the crosstalk between estrogen and androgen receptors.

In their most recent work, Dr Hickey and Dr Tilley used cell-line and patient-derived xenografts to demonstrate that androgen receptor activation by natural androgen or a new androgenic drug had potent antitumor activity in ER-positive breast cancers. They first sampled a piece of the tumor prior to initial surgery and any treatment for the breast cancer. ER-positive samples treated with estrogen alone had higher proliferation compared with patient-matched samples treated with estrogen plus the potent natural androgen 5α-dihydrotestosterone (DHT).

“We developed a technique to take the tumor and cut it into pieces and expose those pieces to drugs for a short amount of time before measuring response,” explained Dr Hickey.

Androgen receptor activation by androgens and the selective androgen receptor agonist enobosarm had potent antitumor activity in all ER-positive breast cancer clinical models tested, including those that had become resistant to ER-targeted endocrine therapy as well as CDK4/6 inhibitors. In addition, Dr Hickey and colleagues used patient-derived xenografts or tumor that has already metastasized.

“These are samples of disease that are most resistant to antiestrogen strategies,” explained Dr Hickey. “Using these models, we showed that androgen receptor activation could potently inhibit cancer growth. At the end-stage of disease, you have new mutations in the ER and other genetic alterations that have gotten the cancer around the current standard of care, but our treatment was still able to knock it out.”