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 2

Estrogens modulate the normal prostate transcriptome in vivo, activating oncogenic pathways similar to those activated with androgen stimulation.

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Estrogens modulate the normal prostate transcriptome in vivo, activating...
(A) Representative IHC images of ERα in normal mouse prostate lobes. Scale bars: 50 μm. Original magnification, ×1.68 (enlarged insets). (B) Quantification of ERα-positive staining and ERα staining intensity in normal mouse prostate lobes (n = ~2,700 cells/animal, n = 5 animals/lobe). (C–I) RNA-Seq analyses of the murine prostate transcriptome 24 hours after injections with vehicle (Ctl), testosterone (Testo), E2, or both (T+E2). Mice were castrated 3 days before injections to ensure hormonal deprivation. (C) Number of significantly differentially expressed genes (DEGs) following pairwise comparisons between conditions. The thresholds used were a fold change of 1.75 or more or –1.75 or less and a P value with a FDR of less than 5%. (D) GSEA normalized enrichment score (NES) following treatment with testosterone. (E and F) GSEA diagrams and heatmaps for the androgen response (E) and the OXPHOS (F) gene sets following testosterone treatment in vivo. (G) GSEA NES for enrichment following E2 treatment in vivo. (H) GSEA diagram and heatmap for the cholesterol homeostasis gene set following E2 treatment. For E, F and H, NESs, P values, and q values are indicated on each diagram, and only core genes of each pathway are shown. *q < 0.05, **q < 0.01, and ***q < 0.001 in GSEA (D and G). (I) Venn diagram of upregulated genes for each pairwise comparison. (J) Venn diagram of estrogen-responsive genes in breast cancer cells (MCF7), using the data set from (41), and in the mouse prostate. Circle and overlap sizes are not proportional to the number of genes. (K) qRT-PCR analysis of positive controls for androgenic (Pfkfb3 and Fkbp11) and estrogenic regulation (Pgr, Fkbp11, and Greb1). For B and K, results are shown as the average with SEM (n = 4 mice/treatment); #P < 0.10; **P < 0.01 and ***P < 0.001, by 1-way ANOVA.