Androgen Receptor Has Potent Antitumor Activity in ER+ Breast Cancer

By Reuters Staff

January 21, 2021

NEW YORK (Reuters Health) - The androgen receptor acts as a potent tumor suppressor in estrogen-receptor-positive (ER+) breast cancer and could be harnessed as an alternative or additive treatment strategy, researchers say.

The need for therapeutic strategies that go beyond endocrine therapy has "renewed interest" in androgen therapy, especially given that nearly all ER+ breast cancers express androgen receptor and nonvirilizing selective androgen receptor modulators are now clinically available, the researchers note in Nature Medicine.

But the role of the androgen receptor in ER+ breast cancer is "controversial, constraining implementation of AR-directed therapies," they point out.

Using cell-line and patient-derived models, Dr. Wayne Tilley of the University of Adelaide, in Australia, and colleagues show that androgen-receptor activation exerts potent anti-tumor activity in ER+ breast cancer, even those resistant to estrogen-receptor and CDK4/6 inhibitors.

"Notably," say the researchers, androgen-receptor agonists combined with standard-of-care agents enhanced therapeutic responses.

"We provide compelling new experimental evidence that androgen receptor stimulating drugs can be more effective than existing (e.g. tamoxifen) or new (e.g. palbociclib) standard-of-care treatments and, in the case of the latter, can be combined to enhance growth inhibition," Dr. Tilley said in a statement.

Mechanistically, activating the androgen receptor with 5alpha-dihydrotestosterone or enobosarm altered the genomic distribution of ER and the essential co-activators p300 and SRC-3, resulting in suppression of ER-regulated cell-cycle genes and upregulation of androgen-receptor target genes, including known tumor suppressors, the researchers report.

Additionally, they say a gene signature of androgen-receptor activity positively predicted disease survival in multiple cohorts of women with ER+ breast cancer.

"This work has immediate implications for women with metastatic ER+ breast cancer," the researchers say.

"These findings provide unambiguous evidence that androgen receptor has a tumor suppressor role in ER-positive breast cancer and support androgen receptor agonism as the optimal androgen receptor-directed treatment strategy, revealing a rational therapeutic opportunity," they conclude.

A phase-3 study evaluating the androgen-receptor-activating agent enobosarm in patients with androgen-receptor and ER positive metastatic breast cancer who failed endocrine therapy and the CDK4/6 inhibitor palbociclib is set to start in the second quarter of 2021 (https://verupharma.com/pipeline/enobosarm/).

This work did not have commercial funding, but one of Dr. Tilley's coauthors has received support from GTx Inc, which provided enobosarm for the study.

Dr. Tilley did not respond to a request for comment by press time.

SOURCE: https://go.nature.com/2XQUtjE Nature Medicine, online January 18, 2021.

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