Terminal differentiation and anti-tumorigenic effects of prolactin in breast cancer

Abstract

Breast cancer is a major disease affecting women worldwide. A woman has 1 in 8 lifetime risk of developing breast cancer, and morbidity and mortality due to this disease are expected to continue to rise globally. Breast cancer remains a challenging disease due to its heterogeneity, propensity for recurrence and metastasis to distant vital organs including bones, lungs, liver and brain ultimately leading to patient death. Despite the development of various therapeutic strategies to treat breast cancer, still there are no effective treatments once metastasis has occurred. Loss of differentiation and increased cellular plasticity and stemness are being recognized molecularly and clinically as major derivers of heterogeneity, tumor evolution, relapse, metastasis, and therapeutic failure. In solid tumors, breast cancer is one of the leading cancer types in which tumor differentiation state has long been known to influence cancer behavior. Reprograming and/or restoring differentiation of cancer cells has been proposed to provide a viable approach to reverse the cancer through differentiation and terminal maturation. The hormone prolactin (PRL) is known to play a critical role in mammary gland lobuloalveolar development/remodeling and the terminal differentiation of the mammary epithelial cells promoting milk proteins gene expression and lactation. Here, we will highlight recent discoveries supporting an anti-tumorigenic role for PRL in breast cancer as a "pro/forward-differentiation" pathway restricting plasticity, stemness and tumorigenesis.

Keywords: JAK/STAT; Prolactin/prolactin receptor; breast cancer; differentiation; plasticity; single cell analysis; stem cells.

Figure 1

PRL induces mammary A/B polarity and acini morphogenesis: Primary mouse mammary epithelial cells grown in 3D culture were stained with antibody to ZO1 (green) and Ecad (red). Nucleus was counter stained with DAPI (blue). Scale bar, 20 µm. The morphology of the colonies was evaluated following different treatments: (1) Control: 2% FBS, (2) PRL: 2% FBS + 2 µg/mL ovine PRL or (3) EGF: 2% FBS + 10 ng/mL EGF. In contrast to control or EGF treated cells, PRL treated mammary epithelial cells organize around a single lumen showing apical localization of the tight junction protein ZO1 and basal/lateral localization of the adhesion protein E-cadherin.

Figure 2

PRL/PRLR signaling pathway in breast cancer differentiation limiting tumorigenesis: The PRL/PRLR pathway is a fundamental pathway promoting mammary gland development, morphogenesis, and terminal differentiation of the mammary epithelial cells. Loss of this hormonal pathway is a marker of aggressive breast cancer characterized by poor differentiation promoting stem-like phenotype, tumor development and metastatic spread.