Despite recent progress in the diagnosis and treatment of breast cancer, this disease remains a leading cause of cancer-related deaths among women. Further understanding of normal mammary gland physiology and how it is disrupted during cancer development and progression will ultimately contribute to improved diagnosis and treatment. Perp, a novel tetraspan membrane protein regulated by the p53 and p63 transcription factors, is known a known effector of apoptosis and cell-cell adhesion and is likely to be important in these contexts. That mammary gland morphogenesis is dependent on p63 and requires both apoptotic and adhesive processes underlies our hypothesis that Perp plays an important role in the proper development of the mammary gland. To test this hypothesis, Perp expression and localization within the mammary epithelium will first be characterized during mouse mammary gland development to define stages at which Perp function may be critical. Next, Perp-null cells will be used to model mammary gland morphogenesis in vitro and in vivo in order to determine how Perp may contribute to this process. Expressing Perp mutants in these contexts will help identify functional domains of Perp and define the mechanism through which it contributes to the appropriate acrchitecture and function of the mammary gland throughout development. Perp-null cells may exhibit defects in apoptosis and/or adhesion, which would likely disrupt the normal structure and function of the developing mammary gland. Such architectural alterations reflect changes fundamental to carcinogenesis, and would suggest a role for Perp in breast cancer. Reduced function of adhesive junctions and apoptotic regulators has been associated with tumorigenic properties in breast cancer cells and poor prognosis in human patients. To assess Perp's in vivo role in breast carcinogenesis, tumor formation and metastasis will be monitored in breat-cancer prone mice with mammary-specific Perp ablation. Together these studies will clarify Perp's role in mammary gland morphogenesis and tumorigenesis. This research will investigate a role for the recently discovered tetraspan membrane protein, Perp, in breast cancer. Important insight into cancer will come from first understanding Perp's role in normal mammary gland biology. The findings have the potential to contribute toward improving the clinical diagnosis, treatment and survival of patients with breast cancer. ? ? ?
| Dusek, Rachel L; Bascom, Jamie L; Vogel, Hannes et al. (2012) Deficiency of the p53/p63 target Perp alters mammary gland homeostasis and promotes cancer. Breast Cancer Res 14:R65 |
