For more than 60–100 years, the treatment of advanced prostate or breast cancer has centered on the blockade of steroid hormone synthesis, the steroid hormone receptors and/or their downstream signaling pathways. The contents of this special focus issue on hormones in breast and prostate cancer in Expert Review of Endocrinology and Metabolism explain why a more contemporary approach is necessary for real progress to be achieved.
In this issue, several authors elaborate on the necessity to develop drugs that block androgen action and agree that there is a need to refine how this is achieved. Professor Fernand Labrie reminds us that prostate cancer is exquisitely sensitive to hormone ablation therapy, but points out the need to revisit the concept of total androgen blockade and when it might be most suitable to introduce this treatment in the management of disease Citation[1]. Regardless of this, and now that it is known that that local androgen synthesis by tumor cells resumes in the castrate setting, there is a compelling rationale to achieve total androgen blockade even in the castrate setting. Implementation of this concept led to the success of drugs like abiraterone, which are a major advance in prostate cancer treatment for men with castration-resistant prostate cancer.
The success of androgen ablation therapy (AAT) has allowed men to live longer and more men are surviving for longer on AAT. However, the complications emerging from such treatments now occur more frequently. The complications the patients develop include bone loss, muscle wasting, diabetes and cardiovascular disease, and have led to the development of specialized clinics for men with ‘prostate cancer complications’, where the adverse effects of androgen deprivation require ongoing management. One adverse risk from AAT is that of bone loss and, in this issue, Souza and Saad describe the phenomenon of bone loss, the risks of ignoring it and their recommendations for patient management Citation[2].
Therefore, in moving forward, Knudsen and Kelly review creative approaches to targeting androgen signaling Citation[3], but the challenge is to develop more sophisticated therapies that specifically target the tumor cells and retain action elsewhere. This approach is warranted in the prostate gland because loss of androgen receptor (AR) in stroma correlates with poor prognosis, and therefore implies that blockade of AR will only exacerbate disease progression Citation[4]. Thus, as we define androgen action in diseased versus healthy prostate tissue, our therapies need to be refined to selectively target the diseased tumor cells, rather than achieve global blockade where nontarget cell androgen action is compromised.
Despite decades of research, we continue to explore and discover new facts about androgen action. The intersection of several factors with androgen signaling pathways feature in this issue and include the IL-6/AR interaction, which is both stimulatory and inhibitory to prostate cancer cells Citation[5]; and the interaction between Gli proteins and AR, which implicates hedgehog and androgen signaling pathways Citation[6]. The role of androgens in epithelial–mesenchymal transition and mesenchymal–epithelial transition provide further need to block androgen action and metastatic spread Citation[7].
Also in this issue, other experts review the need to better understand the role of other steroids and hormones in order to achieve this outcome. Reminding us that while androgens are necessary, they are not sufficient, to cause prostate cancer, Prins et al. review the damaging actions of estrogens and state the case for estrogen blockade, particularly because of the epigenetic changes that are estrogen regulated Citation[8]. A similar case could be made to research the role of progesterone, about which we know very little. Basic research in these areas lags well behind therapies based on androgen action and it is imperative to boost our translational research programs with this focus.
This issue of Expert Review of Endocrinology and Metabolism is a synthesis of different approaches to treatment of prostate as well as breast cancer. A recent review article highlighted some key recent advances in understanding how steroid hormones regulate the growth and survival of breast and prostate cancer as being common to both cancers Citation[9]. These include recognition of the role of local steroid biosynthesis, steroid receptor coregulators and downstream signaling, the importance of stromal components and the effects of the immune system. Each of these elements provides opportunities for new therapeutic approaches that are already showing clinical promise. Ultimately, it is necessary to completely understand how steroid hormones are essential for tumor development before and after hormone-resistant disease occurs. While acknowledging differences between the cancer types, there are common features of breast and prostate cancer (as discussed by Higa in this edition), and undoubtedly more will emerge as the full extent and nature of the hormone regulatory pathways are elucidated, and will provide unique opportunities for new forms of hormone therapy.
This issue of Expert Review of Endocrinology and Metabolism is evidence of the vibrancy of research goals that will underpin the development of new therapies to more effectively treat prostate and breast cancers.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
References
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- De Souza P, Saad F. Bone health in prostate cancer. Expert Rev. Endocrinol. Metab.6(3), 317–321 (2011).
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- Risbridger GP, Davis ID, Birrell SN, Tilley WD. Breast and prostate cancer: more similar than different. Nat. Rev. Cancer10(3), 205–212 (2010).
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