ISM1 plays a pro-tumorigenic role in breast cancer

Abstract

Isthmin 1 (ISM1) is a secreted protein unique to chordates and highly conserved in vertebrates which biological relevance remains largely unexplored. Our previous work found that ISM1 is dynamically expressed in several tissues of the mouse, from early embryonic stages throughout adulthood (Osorio et al., 2014). In addition to its putative role during embryonic and postnatal development, ISM1 may also be important for adult organ homeostasis. ISM1 has been described as an angiogenesis inhibitor that controls tumor size: when ISM1-expressing B16 melanoma cells were injected subcutaneously in the mouse, the tumors formed have a reduced size (Xiang et al., 2011). No further studies have addressed the role of ISM1 in cancer biology. In the present work we aimed at determining the function of ISM1 during mammary gland morphogenesis and its malignant transformation. We generated a BAC ISM1-IRES-EGFP transgenic mouse (ISM1 Tg) and its analyses revealed that ISM1 is present in the mammary tissue all through its ontogeny. ISM1 expression occurs in the KRT14-positive basal myoepithelial cells of the mammary epithelium. Interestingly, ISM1 Tg females show a decreased density of the mammary ductal tree, suggesting an important role of ISM1 in MG morphogenesis. We then examined the role of ISM1 in breast cancer using the MMTV-PyMT mouse model. We found an increased amount of hyperplastic lesions in PyMT;ISM1 Tg females 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. Despite the increased tumor burden, no differences in the cellular composition of the tumors were found, mainly composed by KRT8-positive luminal cells. These results suggest that ISM1 plays a pro-tumorigenic role in breast cancer and the underlying mechanisms are now being investigated. This work has been supported by GRF HKU 787011M and CRCG SFP HKU 201309176176.