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 7

ESR1 expression is increased following ADT, and its transcriptional signature is associated with PCa progression.

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ESR1 expression is increased following ADT, and its transcriptional sig...
(A) Heatmap of the ERα-score in patients from TCGA-PRAD data set (30, 31). The ERα-score is the predicted transcriptional activity of ERα. The legend shows DEGs with increased (red) or decreased (blue) expression following E2 treatment in VCaP cells. (B and C) Kaplan-Meier of BCR-free survival following surgery for patients from TCGA-PRAD (B) and the Taylor et al. (C) data sets, separated by high and low ERα-scores. The log-rank P values are shown. (D) ESR1 (encodes ERα) expression in PCa tumors before and after ADT in the Eur Uro 2017 data set (52). adj, adjusted. (E) ESR1, ESR2, and PGR gene expression in PCa tumors before and after ADT in the Eur Uro 2014 data set (53) (n = 7 paired samples). (F) ESR1, ESR2, and PGR gene expression in PCa tumors before and after ADT plus docetaxel in the BioMed Central (BMC) cancer data set (54) (n = 4 paired samples). (G) ESR1, ESR2, and PGR gene expression in PCa tumors before and after ADT in the GSE183100 data set (n = 73 samples). (H and I) Bright-field images (scale bars: 300 μm) (H) and changes in organoid growth (I) of the PDO 1 line after treatment with vehicle and the anti-androgen enzalutamide (Enza) cotreated or not with E2. (J) ERα-score in the SU2C data set (55), separated by tumor localization in the prostate (n = 5) and metastases in either adrenal glands (n = 2), bone (n = 82), lymph nodes (LN) (n = 79), liver (n = 26), and other sites (n = 14). NS, nonsignificant; *P < 0.05, **P < 0.01, and ***P < 0.001, by 1-way ANOVA (I and J) or 2-tailed Student’s t test, as appropriate (E–G).