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 4

The ERα transcriptional program promotes PCa cell metabolism and proliferation.

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The ERα transcriptional program promotes PCa cell metabolism and prolife...
(A) Western blot of AR and ERα expression in in vitro models: 1 ERα-positive breast cancer cell line (MCF7), 1 ERα-negative mammary gland cell line (MCF10A), and 6 human PCa cell lines (α-tubulin was used as a loading control). exp., exposure. (B–F) RNA-Seq analyses of VCaP cells following 24 hours of treatment with vehicle, the synthetic androgen R1881, E2, or both (R + E2). (B) GSEA NES following treatment with R1881. (C) GSEA diagrams and heatmap for the androgen response gene set following treatment with R1881 and qRT-PCR analysis of KLK3 expression (encodes PSA). Values are shown as the average with the SEM of 4 independent experiments performed in triplicate. (D) GSEA NESs showing enrichment following treatment with E2. #q < 0.05, ##q < 0.01, and ###q < 0.001 (B and D). GSEA diagrams and heatmaps for the OXPHOS (E) and androgen response (F) gene sets following treatment with E2 in VCaP cells. For C, E, and F, the NES, P values, and q values are indicated on each diagram, and only core genes for each pathway are shown. (G) VCaP proliferation assay following treatment with either R1881, E2, or both. One representative experiment of 4 independent experiments is shown. Results are shown as the mean ± SEM (n = 6–8/treatment group). (H) VCaP OCR profiles following 72 hours of treatment with either R1881, E2, or both. Complete mitochondrial stress test results with basal and maximal OCR capacities are shown. Oligo, oligomycin; Rot.+A.A., rotenone + antimycin A. One representative independent experiment of 3 is shown. Data show the mean of normalized data to cell numbers ± SEM (n = 10–12/treatment). *P < 0.05, **P < 0.01, and ***P < 0.001, by 1-way ANOVA (C, G, and H).