Ella Nonni

Introduction: Androgen deprivation therapy is the mainstay of prostate cancer (PCa) treatment¹, however nearly all cases of PCa will eventually become androgen independent or “castration-resistant” (CRPC), at which point five-year survival rates drop from 95% to 28% ². The mechanisms by which prostate tumors continue to proliferate in the absence of androgens is poorly understood, and many possible adaptations are hypothesized. One adaptation may be via estrogen receptors (ERs) in the prostate³. It had previously been hypothesized that ERꞵ has a protective effect on the prostate, and ERα has an oncogenic effect, but subsequent studies demonstrate conflicting evidence³. In this review, five of these recent studies were analyzed and compared to elucidate the role of ERs. Methods: A PubMed search was conducted using the following search terms: castration resistant; prostate cancer; estrogen receptor and filtered to the past five years. Results: The studies reviewed found that: (1) high density of ERα in the tumor stroma was associated with increased time to clinical-failure (p value = 0.042) and PCa death (p value = 0.019) and a high density of ERꞵ was associated with decreased time to biochemical failure (p value = 0.002)³; (2) ERs synergize with ꞵ-catenin  to maintain cancer cell “stemness” and promote CRPC tumor development and chemotherapy resistance⁴; (3) estrogen receptors in the cytoplasm of CRPC cells upregulated ERK signaling pathway which promotes tumor cell proliferation⁵; (4) ERꞵ activation with a high-affinity synthetic estrogen decreased androgen receptor (AR) expression (>70% reduction in AR mRNA, protein and splice variants) and increased tumor cell apoptosis by 3-5 fold in brink-of-therapy-resistance cells in vivo⁶; and (5) activation of estrogen-related receptor alpha (ERRɑ) promotes bone metastasis in CRPC in vivo⁷. Conclusion: Recent studies have confirmed that estrogen receptors do play a significant role in the regulation of tumor progression and metastasis in CRPC, and findings are promising for clinical application, however the results continue to conflict. In three of the studies, an upregulation of either type of ER resulted in accelerated tumor progression^4,5,7;  but in another, high-density of stromal ERα was associated with improved prognosis³. High-density of ERꞵ in tumor stroma was associated with worsened prognosis³, yet in another study upregulation of ERꞵ significantly decreased tumor progression⁶. The conditions under which ERs influence CRPC outcomes should be fully determined before a clinical application is developed.

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4. Lombardi APG, Vicente CM, Porto CS. Estrogen Receptors Promote Migration, Invasion and Colony Formation of the Androgen-Independent Prostate Cancer Cells PC-3 Through β-Catenin Pathway. Front Endocrinol (Lausanne). 2020;11:184. Published 2020 Apr 9. doi:10.3389/fendo.2020.00184
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6. Gehrig J, Kaulfuß S, Jarry H, et al. Prospects of estrogen receptor β activation in the treatment of castration-resistant prostate cancer. Oncotarget. 2017;8(21):34971-34979. doi:10.18632/oncotarget.16496
7. Fradet A, Bouchet M, Delliaux C, et al. Estrogen related receptor alpha in castration-resistant prostate cancer cells promotes tumor progression in bone. Oncotarget. 2016;7(47):77071-77086. doi:10.18632/oncotarget.12787