Nuclear Estrogen Receptors in Prostate Cancer: From Genes to Function

Abstract

Estrogens are almost ubiquitous steroid hormones that are essential for development, metabolism, and reproduction. They exert both genomic and non-genomic action through two nuclear receptors (ERα and ERβ), which are transcription factors with disregulated functions and/or expression in pathological processes. In the 1990s, the discovery of an additional membrane estrogen G-protein-coupled receptor augmented the complexity of this picture. Increasing evidence elucidating the specific molecular mechanisms of action and opposing effects of ERα and Erβ was reported in the context of prostate cancer treatment, where these issues are increasingly investigated. Although new approaches improved the efficacy of clinical therapies thanks to the development of new molecules targeting specifically estrogen receptors and used in combination with immunotherapy, more efforts are needed to overcome the main drawbacks, and resistance events will be a challenge in the coming years. This review summarizes the state-of-the-art on ERα and ERβ mechanisms of action in prostate cancer and promising future therapies.

Unveiling hormone‐stimulated gene mechanisms in prostate cancer: A prognostic model, immune infiltration analysis, and drug sensitivity study

“…6 However, reactivation of AR signaling may lead to the progression to CRPC, thus severely limiting the long-term efficacy of ADT. 7 Furthermore, some patients may progress to NEPC after receiving ADT and other treatments. NEPC lacks AR and PSA expression and is less responsive to the existing treatment regimens.…”

“…Nevertheless, a significant proportion of patients experience recurrence and distant metastasis due to the substantial biological heterogeneity of PRCA, which diminishes survival rates and quality of life. 5 The initiation and progression of PRCA is driven by hormones such as androgens, 6 estrogens, 7 glucocorticoids, 6 and insulin-like growth factor. 8 Androgens are the primary stimulators of PRCA, and most androgens are synthesized by the testicular interstitial, while smaller amounts are synthesized by the adrenal glands.…”

Long-Term Exposure to Supraphysiological Levels of Testosterone Impacts Rat Submandibular Gland Proteome

“…Estrogen can either be locally synthesized within the prostate or derived from the systemic circulation. When estrogen binds to ERs, it triggers signaling pathways that affect proliferation, apoptosis, and inflammation [ 61 , 62 , 63 ]. The interaction between the AR and ER signaling pathways is complex, and they can impact each other’s activity.…”

Novel frontiers in urogenital cancers: from molecular bases to preclinical models to tailor personalized treatments in ovarian and prostate cancer patients

“…Progesterone can activate canonical and non-canonical AR target genes, and inhibition of 3b-hydroxysteroid dehydrogenase 1 (3bHSD1) can suppress the oncogenic effects of progesterone [ 164 ]. Prostate tissues express both ERα and ERβ [ 165 ] and PC development depends also on estrogen signaling. Estrogen can increase the occurrence of androgen-induced PC [ 166 ].…”