Prolactin hormone exerts anti-tumorigenic effects in HER-2 overexpressing breast cancer cells through regulation of stemness

Abstract

Background: Breast cancers characterized by HER2 overexpression, belong to HER-2 enriched or luminal B subtypes, are frequently associated with higher incidence of tumor recurrence and therapeutic failure. These aggressive features have been attributed to the presence of cancer stem-like cell subpopulations known to have high tumor initiation, self -renewal capacities and high metastatic potential. Depleting these stem-like cells in these tumors therefore might help in improving therapeutic response and patient outcome. Methods: Here we used human breast cancer cells representative of HER2- enriched and luminal B subtypes as well as purified ALDH-positive stem-like cell subpopulation for in vitro cell viability, proliferation, tumorshpere formation analyses and gene expression studies. In addition, we used a pre-clinical xenograft HER2 mouse model (NOD/SCID mice) for in vivo tumorigenesis assessment. Furthermore, patient survival outcomes were evaluated using in silico bioinformatics analyses of publicly available datasets. Results: Our results indicate that prolactin (PRL) exerts anti-tumorigenic effects in HER-2 positive breast cancer cells. Importantly, PRL caused a significant reduction in ALDHhi stem-like subpopulation, as well as their viability and tumorsphere formation capacity. Molecularly we found PRL to suppress gene expression of markers involved in stemness, tumor initiation, drug resistance and poor patient outcome found to be enriched in the ALDHhi stem-like subpopulation. Furthermore, we show PRL to impede tumor growth of HER-2 xenografts and to suppress expression of Ki67 proliferative marker. Finally, we found PRL pathway gene signature to correlate with favorable patient outcomes in HER-2 and luminal B breast cancer patients. Conclusion: Together these results emphasize an anti-tumorigenic role with a potential therapeutic value for PRL in HER-2 and luminal B breast cancer subtypes targeting the cancer stem-like cells. Keywords: Differentiation, Stem cells, Lactation