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A novel clinically relevant antagonistic interplay between prolactin and oncogenic YAP-CCN2 pathways as a differentiation therapeutic target in breast cancer

Published on Friday, 29 August 2025

Abstract

Cellular differentiation limits cellular plasticity allowing cells to attain their specialized functional characteristics and phenotypes, whereas loss of differentiation is a hallmark of cancer. Thus, characterizing mechanisms underlying differentiation is key to discover new cancer therapeutics.

We report a novel functional antagonistic relationship between the prolactin (PRL)/prolactin receptor (PRLR) differentiation pathway and YAP-CCN2 oncogenic pathway in normal mammary epithelial cells and breast cancer cells that is essential for establishing/maintaining acinar morphogenesis, cell-cell junctions and the intracellular localization of apical-basal polarity protein complexes (Par, Crumb and Scrib).

Importantly, using CRISPR knockout of the PRLR in MCF7, HR+ breast cancer cells, further revealed that the negative relationship between PRL/PRLR pathway and YAP-CCN2 pathway is critical in suppressing luminal-to-basal stem-like lineage plasticity.

Furthermore, the clinical relevance of this interplay was evaluated using bioinformatics approaches on several human datasets, including samples from normal breast epithelium, breast cancer, and 33 other cancer types.

This analysis revealed a positive correlation between PRLR and the YAP suppressor Hippo pathway and a co-expression gene network driving favourable patients' survival outcomes in breast cancer.

The therapeutic potential of this interplay was also evaluated in vitro using MDA-MB-231 cells, a preclinical model of human triple-negative breast cancer, where treatment with PRL and Verteporfin, an FDA-approved pharmacological YAP-inhibitor, alone or their combination suppressed the expression of the mesenchymal marker vimentin and the stem cell marker CD44 as well as reduced their Ki67 proliferative marker expression.

Collectively, our results emphasize the pro-differentiation role of PRL/PRLR pathway in mammary and breast cancer cells and highlight that promoting PRL/PRLR signaling while inhibiting the YAP-CCN2 oncogenic pathway can be exploited as a differentiation-based combination therapeutic strategy in breast cancer.

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About this publication.

The Di Bella's Method: Use of Cabergoline and/or Bromocriptine, Estrogen therapy (Anastrozole 1 mg tab per day), pseudo-Metronomic Chemotherapy Cyclophosphamide and/or Hydroxyurea with Somatostatin/Octreotide analogues and/or derivatives (together with others chemical compounds) in Breast Cancer:

- A retrospective observational clinical study of triple negative breast cancer cases treated with Di Bella Method: A preliminary data;

- The Synergism of Somatostatin, Melatonin, Vitamins Prolactin and Estrogen Inhibitors Increased Survival, Objective Response and Performance Status In 297 Cases of Breast Cancer;

- Complete objective response, stable for 5 years, with the Di Bella Method, of multiple-metastatic carcinoma of the breast;

- Evaluation of the safety and efficacy of the first-line treatment with somatostatin combined with melatonin, retinoids, vitamin D3, and low doses of cyclophosphamide in 20 cases of breast cancer: a preliminary report;

- The Di Bella Method (DBM) improved survival, objective response and performance status in a retrospective observational clinical study on 122 cases of breast cancer;

- Complete objective response to biological therapy of plurifocal breast carcinoma;

- The Di Bella Method (A Fixed Part - Bromocriptine and/or Cabergoline);

- Prolactin inhibitors in oncology - In vitro, review and in vivo publications;

- The Di Bella Method (A Fixed Part - Cyclophosphamide 50mg tablets and/or Hydroxyurea 500mg tablets, one or two per day);

- The Di Bella Method (A Fixed Part - Somatostatin, Octreotide, Sandostatin LAR, analogues and/or derivatives);

- Somatostatin in oncology, the overlooked evidences - In vitro, review and in vivo publications;

- Publication, 2018 Jul: Over-Expression of GH/GHR in Breast Cancer and Oncosuppressor Role of Somatostatin as a Physiological Inhibitor (from Di Bella's Foundation);