Endocrine Abstracts

Androgen-independent recurrence is the major limit of androgen ablation therapy for prostate cancer. Identification of alternative pathways promoting prostate tumor growth is thus needed. Signal transducer and activator of transcription 5 (Stat5) has been recently shown to promote human prostate cancer cell survival/proliferation and to be associated with early prostate cancer recurrence. Stat5 is the main signaling pathway triggered by prolactin (PRL), a polypeptide hormone mainly secreted by the pituitary. PRL is also expressed by prostate epithelial cells, and increased PRL expression has been documented in high-grade prostate cancers. Prostate-specific PRL transgenic mice were earlier reported to develop benign prostate hyperplasia (BPH). We have used these mice to address the mechanisms by which local PRL induces prostate tumorogenesis. We observed that i) Stat5 is the major signaling cascade triggered by local PRL in the mouse dorsal prostate, ii) this model actually recapitulates prostate tumorogenesis from pre-cancer lesions in young animals, to invasive carcinoma in older mice, iii) tumorogenesis involves dramatic accumulation and abnormal spreading of p63-positive basal cells, and of stem cell antigen-1 positive cells identified as a stem/progenitor-like subpopulation. Since basal epithelial stem cells have been proposed to serve as tumor-initiating cells, we challenged the relevance of local PRL as a novel therapeutic target. Using a double transgenic approach, we show that Del1-9-G129R-hPRL, a competitive PRL receptor antagonist developed by our group, prevents early stages of prostate tumorogenesis by reducing or inhibiting Stat5 activation, cell proliferation, abnormal basal cell pattern and frequency/grade of intraepithelial neoplasia.

Although PRL is currently viewed by clinical endocrinologists as a pituitary hormone whose unique associated pathology is hyperprolactinemia leading to reproductive disorders, our study identifies autocrine PRL/Stat5 as a novel pathway initiating prostate tumorogenesis by altering basal/stem-like cell subpopulations. These findings strongly support the importance of further developing strategies to target locally over-expressed PRL in human prostate cancer, which cannot be achieved using current anti-PRL approaches involving dopamine agonists.