The estrogen signaling pathway reprograms prostate cancer cell metabolism and supports proliferation and disease progression
Camille Lafront, … , Éric Lévesque, Étienne Audet-Walsh
Camille Lafront, … , Éric Lévesque, Étienne Audet-Walsh
Published April 16, 2024
Citation Information: J Clin Invest. 2024;134(11):e170809. https://doi.org/10.1172/JCI170809.
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Research Article Endocrinology Oncology

The estrogen signaling pathway reprograms prostate cancer cell metabolism and supports proliferation and disease progression

Abstract

Just like the androgen receptor (AR), the estrogen receptor α (ERα) is expressed in the prostate and is thought to influence prostate cancer (PCa) biology. Yet the incomplete understanding of ERα functions in PCa hinders our ability to fully comprehend its clinical relevance and restricts the repurposing of estrogen-targeted therapies for the treatment of this disease. Using 2 human PCa tissue microarray cohorts, we first demonstrate that nuclear ERα expression was heterogeneous among patients, being detected in only half of the tumors. Positive nuclear ERα levels were correlated with disease recurrence, progression to metastatic PCa, and patient survival. Using in vitro and in vivo models of the normal prostate and PCa, bulk and single-cell RNA-Seq analyses revealed that estrogens partially mimicked the androgen transcriptional response and activated specific biological pathways linked to proliferation and metabolism. Bioenergetic flux assays and metabolomics confirmed the regulation of cancer metabolism by estrogens, supporting proliferation. Using cancer cell lines and patient-derived organoids, selective estrogen receptor modulators, a pure anti-estrogen, and genetic approaches impaired cancer cell proliferation and growth in an ERα-dependent manner. Overall, our study revealed that, when expressed, ERα functionally reprogrammed PCa metabolism, was associated with disease progression, and could be targeted for therapeutic purposes.

Authors

Camille Lafront, Lucas Germain, Gabriel H. Campolina-Silva, Cindy Weidmann, Line Berthiaume, Hélène Hovington, Hervé Brisson, Cynthia Jobin, Lilianne Frégeau-Proulx, Raul Cotau, Kevin Gonthier, Aurélie Lacouture, Patrick Caron, Claire Ménard, Chantal Atallah, Julie Riopel, Éva Latulippe, Alain Bergeron, Paul Toren, Chantal Guillemette, Martin Pelletier, Yves Fradet, Clémence Belleannée, Frédéric Pouliot, Louis Lacombe, Éric Lévesque, Étienne Audet-Walsh

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Figure 1

ERα expression is heterogenous in PCa and, when nuclear (active), is associated with BCR.

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ERα expression is heterogenous in PCa and, when nuclear (active), is ass...
(A) Kaplan-Meier of BCR-free survival following radical prostatectomy in patients from TCGA-PRAD cohort with high or low ERα protein expression levels (no distinction between nuclear and cytoplasmic localization). (B) Proportions of patients from TCGA cohort with high or low ERα protein expression levels, with and without BCR (**P < 0.0019, χ2 test). (C–F) Analysis of the Belledant et al. (32) cohort. (C) Representative images of ERα IHC in 4 patients with PCa. Black and red arrows, respectively, highlight negative and positive staining. Scale bars: 50 μm. Original magnification, ×3.1 (enlarged insets in C and G). (D) Kaplan-Meier BCR-free survival following radical prostatectomy in patients with positive versus negative nuclear levels of ERα. (E) Proportions of patients from the TMA cohort with positive or negative nuclear levels of ERα, with and without BCR (***P < 0.001, χ2 test). (F) Cox regression analyses of the effect of positive (Pos.) nuclear ERα levels on the risk of BCR (*P < 0.05, **P < 0.01, and ***P < 0.001). Boxes illustrate HRs with their respective 95% CIs. Results are shown without (left) and with (right) additional BCR risk factors. Reference groups for covariables: Gleason score of 6; T2c stage and below; presurgery PSA levels under 10 ng/mL; negative lymph node invasion and negative margins. (G–I) Analysis of an independent cohort of patients who received neoadjuvant hormonotherapy before surgery. (G) Representative IHC images of ERα expression in 4 patients with PCa. Black and red arrows, respectively, highlight negative and positive staining. Scale bars: 50 μm. (H and I) Kaplan-Meier survival analysis in patients with positive versus negative (Neg.) ERα nuclear levels in the development of metastasis (H) and overall survival (I). For Kaplan-Meier survival curves, the log-rank test P value is shown in the inset.