New research shows testosterone promotes melanoma proliferation by activating a newly recognized unclassical testosterone receptor in melanoma cells called ZIP9 (encoded by the SLC39A9 gene), a zinc transporter that is not intentionally targeted by any therapy available but which is widely expressed in human melanoma. New study by researchers at the University of Pennsylvania’s Perelman School of Medicine uses models of melanoma in mice to show that drugs that target androgen receptors (ARs) in prostate cancer can be effectively reused to block ZIP9 and thus inhibit melanoma in men. The results were published today in the journal Research against cancer.

Melanoma and most other cancers occur more frequently and have worse consequences in men than in women. The American Cancer Society estimates that approximately 106,110 new melanomas will be diagnosed (approximately 62,260 in men and 43,850 in women) in the United States by 2021, and approximately 7,180 people are expected to die from the disease (approximately 4,600 men and 2,580 women). Although this gender difference has been recognized for decades, the reasons for this difference have remained largely elusive. Although sex steroids are involved, the classic androgen and estrogen receptors generally considered necessary for the effects of sex steroids are not detectable in most melanomas.

Testosterone, a male sex hormone, increases the rate of melanoma cell proliferation because it works through ZIP9 rather than through the classic testosterone receptors that are well studied in prostate cancer. While there are no approved drugs that inhibit ZIP9, structurally related drugs such as apalutamide that block the classic testosterone / androgen receptor in prostate cancer, when given to affected mice melanoma, slow tumor growth and prolong survival, but only in males. “

Todd Ridky, MD, PhD, senior author, associate professor of dermatology at Penn

This finding about ZIP9 is probably applicable to most human melanomas. The study examined 98 human melanocytic lesions (regular moles, as well as primary and metastatic melanoma in men and women). Almost all of the samples expressed a lot of ZIP9, while the classic testosterone receptor was not detectable in any of them. ZIP9 is also expressed in many other human tissues, suggesting that this finding in melanoma may be widely applicable to many types of cancer.

This study is the first to show that ZIP9 is a determinant of the disparity between men and women in cancer, and establishes a new mechanistic link between male androgens and the pathobiology of melanoma. These findings also build on previous work from Penn’s Ridky Lab, where researchers have shown that estrogen signaling through an unclassical estrogen receptor called the G-Protein Coupled Estrogen Receptor (GPER) suppresses melanoma. and other cancers.

When it comes to certain cancers and sex hormones, biological males appear to be doubly disadvantaged: they lack the protective effects of unconventional estrogen activity, while testosterone, via ZIP9, actively aggravates tumors. The potential good news is that both of these sex steroid receptors are likely medicated. Although more clinical trials are needed, currently approved prostate cancer drugs appear to effectively block ZIP9.