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Just like the androgen receptor (AR), the estrogen receptor [alpha] (ER[alpha]) is expressed in the prostate and is thought to influence prostate cancer (PCa) biology. Yet the incomplete understanding of ER[alpha] 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 ER[alpha] expression was heterogeneous among patients, being detected in only half of the tumors. Positive nuclear ER[alpha] 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 ER[alpha]-dependent manner. Overall, our study revealed that, when expressed, ER[alpha] functionally reprogrammed PCa metabolism, was associated with disease progression, and could be targeted for therapeutic purposes., Introduction Prostate cancer (PCa) is the most common cancer for men in 112 countries (1). This disease is highly dependent on the androgen receptor (AR), a transcription factor that modulates [...]