The human intermediate prolactin receptor is a mammary proto-oncogene

Area of Science:

• Oncology
• Molecular Biology
• Endocrinology

Background:

• Prolactin (PRL) and its receptor (hPRLr) play roles in breast cancer.
• An alternatively-spliced intermediate hPRLr (hPRLrI) isoform promotes cell viability and proliferation.
• A similar truncated mouse PRL receptor (mPRLr) was found to be oncogenic.

Purpose of the Study:

• To investigate if hPRLrI co-expression with hPRLrL transforms human breast epithelial cells.
• To elucidate the mechanism of hPRLrI-mediated transformation.

Main Methods:

• Co-expression of hPRLrL and hPRLrI in MCF10AT cells.
• hPRLrI knockdown in MCF7 cells.
• Analysis of hPRLrL+I heterodimer stability and signaling pathways (Jak2, Ras, MAPK, Stat5a).
• Immunohistochemical analysis of breast cancer tissue microarrays.
• RNA sequencing analysis using The Cancer Genome Atlas (TCGA).

Main Results:

• hPRLrL+I co-expression induced robust in vivo and in vitro transformation of MCF10AT cells.
• hPRLrI knockdown significantly reduced the malignant potential of MCF7 cells.
• hPRLrL+I heterodimers were more stable than hPRLrL homodimers.
• hPRLrL+I activated Jak2, Ras, and MAPK but not Stat5a.
• Higher hPRLrI expression correlated with triple-negative breast cancer (TNBC).

Conclusions:

• The hPRLrI isoform, alongside hPRLrL, contributes to mammary transformation.
• This represents a novel oncogenic mechanism in breast cancer.
• hPRLrI is associated with triple-negative breast cancer, suggesting its potential as a therapeutic target.