A novel clinically relevant antagonistic interplay between prolactin and oncogenic YAP-CCN2 pathways as a differentiation therapeutic target in breast cancer
- Xueqing Liu 1, Alaa Moamer 1, Roger Gomes da Silva 1, Aidan Shoham-Amizlev 1, Dana Hamam 1, Anwar Shams 1,2, Jean-Jacques Lebrun 1, Suhad Ali 3
- 1Department of Medicine, Cancer Research Program, Centre for Translational Biology, McGill University Health Centre, McGill University, Montreal, QC, Canada.
- 2Department of Pharmacology, College of Medicine, Taif University, Taif, Saudi Arabia.
- 3Department of Medicine, Cancer Research Program, Centre for Translational Biology, McGill University Health Centre, McGill University, Montreal, QC, Canada. suhad.ali@mcgill.ca.
- 0Department of Medicine, Cancer Research Program, Centre for Translational Biology, McGill University Health Centre, McGill University, Montreal, QC, Canada.
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View abstract on PubMed
Summary
This summary is machine-generated.The prolactin (PRL) pathway promotes differentiation and suppresses stem-like plasticity in breast cells by antagonizing the YAP-CCN2 pathway. This interplay offers a novel differentiation-based therapeutic strategy for breast cancer.
Area Of Science
- Cellular biology
- Cancer research
- Endocrinology
Background
- Cellular differentiation is crucial for specialized function; its loss is a hallmark of cancer.
- Understanding differentiation mechanisms is key to developing new cancer therapeutics.
- The prolactin (PRL)/prolactin receptor (PRLR) pathway and the YAP-CCN2 pathway play roles in cell plasticity and cancer.
Purpose Of The Study
- To investigate the functional relationship between the PRL/PRLR and YAP-CCN2 pathways in mammary epithelial and breast cancer cells.
- To determine the role of this interplay in acinar morphogenesis, cell junctions, and polarity.
- To explore the therapeutic potential of modulating these pathways in breast cancer.
Main Methods
- CRISPR-Cas9 knockout of PRLR in MCF7 cells.
- Bioinformatics analysis of human breast tissue and cancer datasets.
- In vitro treatment of MDA-MB-231 cells with PRL and Verteporfin.
Main Results
- A novel antagonistic relationship was identified between the PRL/PRLR and YAP-CCN2 pathways, crucial for acinar morphogenesis and polarity.
- PRLR knockout promoted stem-like lineage plasticity.
- Bioinformatics analysis showed a positive correlation between PRLR and the Hippo pathway, linked to favorable patient survival.
- Combination therapy with PRL and Verteporfin suppressed mesenchymal and stem cell markers and reduced proliferation in triple-negative breast cancer cells.
Conclusions
- The PRL/PRLR pathway promotes differentiation and suppresses stem-like plasticity in mammary and breast cancer cells.
- Targeting the PRL/PRLR pathway and inhibiting YAP-CCN2 concurrently represents a promising differentiation-based combination therapy for breast cancer.
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