ISM1 in mammary gland morphogenesis and its malignant transformation

Abstract

Isthmin 1 (ISM1) is a secreted protein dynamically expressed from early embryonic stages throughout adulthood (Osorio et al., 2014). In the mouse, ISM1 is present in particular epithelial cell populations of the respiratory, digestive and reproductive systems, suggesting that ISM1 may contribute to organ ontogeny and homeostasis. The biological relevance of ISM1 remains largely unexplored. ISM1 has been described as an angiogenesis inhibitor that controls endothelial cell survival through integrin signaling (Xiang et al., 2011; Zhang et al., 2011). No other studies have addressed the role of ISM1 in epithelia and/or cancer biology. In the present work we aimed at determining the function of ISM1 during mammary gland (MG) morphogenesis and its malignant transformation. ISM1 is present in the mammary tissue all through its ontogeny. ISM1 expression occurs in the basal myoepithelial cells of the mammary epithelium as well as in the surrounding stromal cells. Analyses of BAC ISM1-IRES-EGFP transgenic females (ISM1 Tg) show a defective branching morphogenesis. We then examined ISM1 in breast cancer using the MMTV-PyMT mouse model. We found an increased amount of hyperplastic lesions in PyMT;ISM1 Tg at 4 weeks old. Consistently, both the number and total weight of tumors per mouse is increased by more than 2-fold in PyMT;ISM1 Tg mice at later stages. In addition, tumor cells in PyMT;ISM1 Tg mice are easier to metastasize to the lungs. We are currently investigating the mechanism(s) mediating the function of ISM1.