PTP1B restrains mammary progenitor cells fate commitment and secretory differentiation

Abstract

Protein tyrosine phosphatase 1B (PTP1B) is a member of the classical tyrosine phosphatase family, which modulates diverse biological processes including proliferation, differentiation, apoptosis and migration. PTP1B is a major regulator of cell metabolism. It decreases insulin signaling by dephosphorylating the insulin receptor and IRS proteins, and attenuates leptin action by dephosphorylating JAK2. Identifying PTP1B as an important target in diabetes and obesity. PTP1B has received additional attention because several studies revealed a role for PTP1B in different types of cancer, including breast neoplasia. PTP1B is overexpressed in human breast cancer, and depletion of PTP1B delays mammary tumorigenesis in mouse models of mammary cancer induced by activated ERBB2. However, relatively little was known about the normal physiological role of PTP1B in the mammary gland before this study. PTP1B was suggested to play a role in normal mammary gland development by regulating the prolactin-mediated activation of STAT5, a key regulator of mammary gland development and differentiation. While informative, these findings were based on knockdown experiments in breast cancer cell lines, which may not accurately reflect the in vivo situation. Therefore, in this study we took advantage of a PTP1B knockout mouse model to gain a deeper knowledge on the role of this phosphatase plays in mammary cell fate and mammary gland development. We found that loss of PTP1B increases the number of mammary alveolar progenitors, enhancing the pool of cells able to generate alveolar structures during pregnancy. Consistently, we observed an increase in alveolar density in glands from PTP1B-/- mice. We also found that deletion of PTP1B increased expression of milk proteins during late pregnancy. We showed that these phenotypes are mediated by precocious phosphorylation and activation of the transcription factor STAT5 and/or by increased expression of the progesterone receptor, two key regulators of mammary gland development and differentiation. These observations provide new insight into the signaling cascades that regulate mammary stem/progenitor cells differentiation and lineage commitment during mammary gland development. In summary, we identified new functions for PTP1B in mammary gland alveologenesis and lactogenesis. The absence of PTP1B protects from, or delays HER2/Neu evoked mammary tumors in mice. Our studies raise the possibility that the change in mammary cell fate seen in glands lacking PTP1B may contribute to the observed cancer protective effect, a question that warrant further investigation.