The following is a summary of “Human Intermediate Prolactin Receptor I-tail Contributes Breast Oncogenesis by Targeting Ras/MAPK Pathway,” published in the June 2024 issue of Endocrinology by Shen, et al.

Prolactin (PRL) and its receptor (PRLr) play significant roles in breast cancer pathogenesis in humans. An intermediate form of the human PRLr (hPRLrI), generated via alternative splicing, features a unique 13 amino acid “I-tail” extension. Coexpression of hPRLrL (long form) and hPRLrI induces robust proliferation and anchorage-independent growth of normal mammary epithelial cells in vitro. Furthermore, in vivo studies demonstrated that both forms are necessary for inducing mammary epithelial transformation. The I-tail of hPRLrI interacts with neural precursor cell expressed developmentally downregulated protein 8 (NEDD8), a ubiquitin-like protein. Inhibition of NEDD8-activating enzyme with pevonedistat increases hPRLrL levels and induces apoptosis in breast cancer cells.

For a study, researchers sought to elucidate the specific function of the hPRLrI I-tail in hPRLrL/hPRLrI-mediated mammary transformation. Introduction of hPRLrL/hPRLrI and a mutant lacking the I-tail (hPRLrL/hPRLrIΔ13) into MCF10AT cells revealed that removal of the I-tail decreased cell proliferation. Additionally, deletion of the I-tail reduced anchorage-independent growth and attenuated cell migration. Mechanistically, the I-tail influenced Ras/MAPK signaling but not the PI3K/Akt pathway, as demonstrated by western blot analysis. Removal of the I-tail led to decreased stability of hPRLrI. RNA-sequencing data showed that deletion of the I-tail altered prolactin-induced gene expression profiles. Ingenuity Pathway Analysis revealed that ERK activity was diminished upon I-tail removal. Treatment of breast cancer cells with the ERK1/2 inhibitor ulixertinib resulted in reduced colony-forming ability and proliferation.

In conclusion, the findings suggested that the hPRLrI I-tail plays a crucial role in breast oncogenesis. Targeting the I-tail may hold promise for developing novel therapies for breast cancer.

Reference: academic.oup.com/endo/article-abstract/165/6/bqae039/7666235