Targeting sex steroid biosynthesis for breast and prostate cancer therapy

: Poutanen Matti, Hagberg Thulin Malin, Härkönen Pirkko

Publisher: NATURE PORTFOLIO

: 2023

: Nature Reviews Cancer

: NATURE REVIEWS CANCER

: NAT REV CANCER

: 23

: 10

: 686

: 709

: 24

: 1474-175X

: 1474-1768

DOI: https://doi.org/10.1038/s41568-023-00609-y

: https://doi.org/10.1038/s41568-023-00609-y

Sex steroids are major promoters of the growth of breast and prostate cancers. This Review by Poutanen et al. describes the development of treatments for these cancer types that act to restrict sex steroid availability for receptor binding by inhibiting steroid biosynthesis, being a complementary mechanism of action to the more traditional sex steroid antagonists.Sex steroids, such as androgens and oestrogens, are hormones that primarily regulate the physiology of reproductive organs and maintain reproductive capacity in both men and women, respectively. Later in life, these sex steroids can become major promoters of the growth of cancer in the reproductive tissues, such as the breast and prostate, with breast cancer being the most common cancer in women and prostate cancer being the second most common cancer in men. Oestrogens and androgens act via specific receptor proteins that act as steroid-activated transcription factors. Accordingly, all current endocrine therapies for breast and prostate cancer target steroid-receptor interactions either directly or indirectly. These therapies encompass compounds that inhibit gonadotropin-regulated steroid biosynthesis in the gonads, antagonists and degraders of oestrogen and androgen receptors, and inhibitors of enzymes of oestrogen and androgen biosynthesis. Such enzyme inhibitors can reduce the concentration of potent oestrogens and androgens and their precursors in the tumours by blocking their gonadal and adrenal production, by hindering the activation of the blood-transported precursors within the tumours and/or by inhibiting any local de novo steroid biosynthesis in the tumours. Some well-characterized inhibitors of enzymes of the classical biosynthesis routes of oestrogens and androgens are used in the treatment of breast and prostate cancer, and novel compounds are in development. However, it is likely that not all enzymes involved in sex steroid biosynthesis have been discovered. Furthermore, novel biologically active sex steroids, such as 11-oxygenated androgens, have been more recently identified. Accordingly, so-far-unidentified targets and novel mechanisms for inhibiting sex steroid biosynthesis are expected to provide further tools for more efficient therapies for sex steroid-dependent breast and prostate cancer.