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 6

SERMs and fulvestrant inhibit E2-dependent stimulation of mitochondrial respiration, proliferation, and growth of PCa cells.

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SERMs and fulvestrant inhibit E2-dependent stimulation of mitochondrial ...
(A) VCaP OCR profiles following a 72-hour treatment with E2, tamoxifen (Tamox), raloxifene (Ralox), toremifene (Torem), and fulvestrant (Fulv). Results from a complete mitochondrial stress test of 1 experiment are presented, with basal and maximal OCR capacities shown as the average of 2 of 3 independent experiments. Data indicate the mean ± SEM (n = 8–12/treatments per experiment). Changes in VCaP cell number following 168 hours of treatment with anti-estrogens cotreated with E2 (B), or with hormone cotreatment with fulvestrant or enzalutamide (C), normalized to control. One representative experiment of 3 independent experiments is shown. Data indicate the mean ± SEM (n = 6–8/condition). (D) Kaplan-Meier of survival and tumor growth of castrated mice with VCaP xenografts under either a placebo or E2 pellet treatment and injected weekly with vehicle or fulvestrant (n = 5–10 mice/condition). The log-rank test P value is shown. Changes in tumor growth were quantified on the basis of tumor volume at castration adjusted at 0%. Tumor growth is shown up to 90 days, at which point most E2-treated tumors were harvested. Colored arrows indicate mice reaching ethical limit points. (E and F) Bright-field images (E) and changes in organoid growth (F) of 3 PDO lines after 14–15 days of treatment with vehicle, E2, fulvestrant, or both. (G) qRT-PCR analysis of ESR1 expression in the PDO lines shown in E. Results are shown as a fold change compared with PDO 3. (H and I) Bright-field images (H) and changes in organoid growth (I) in PDO 1 after 15 days of treatment with vehicle and E2, with and without ESR1 knockdown. Scale bars: 300 μm (E and H). Results in F and I are shown as the mean ± SEM (n = 4 replicates/condition). NS, nonsignificant; *P < 0.05, **P < 0.01, and ***P < 0.001, by 1-way ANOVA.