Abstract 3681: Nischarin disruption promotes breast tumor development in mouse models

Abstract

Abstract Nischarin is a novel tumor suppressor that was first discovered and characterized in our laboratory. The accumulating evidence suggests that Nischarin is a critical regulator of cell migration and breast tumor growth, metastasis and invasion. However, little is known about the exact function of Nischarin in in vivo physiological conditions, probably due to lack of any transgenic Nischarin animals. We recently generated Nischarin knockout mouse. This Nischarin knockout mouse has a dramatic unusual phenotype of mammary development and overall growth defect. Nischarin knockout mice do not spontaneously develop breast tumors. To determine the importance of Nischarin in regulation of breast cancer development, we bred Nischarin knockout virgin mice with PyMT (polyoma middle T antigen) and Neu background mice and the progeny produced tumors exclusively in the mammary gland. We found Nischarin knockout virgins with PyMT accelerated breast cancer onset and progression, which further suggests Nischarin inhibits tumor growth. Mammary epithelial cells (MECs) are surrounded by basement membrane, which mainly consists of extracellular matrix. We noted that the basement membrane of Nischarin knockout virgins contain much more collagen and fibronectin than those of wild type virgins. In addition, we observed that Nischarin disruption significantly changed extracellular acidification rates (ECAR) in mouse primary breast tumour cells. We suspected that this changed acidic microenvironment might facilitate breast tumor progression. Recent studies indicated that clinical anti-diabetic drug Metformin, an AMPK activator, inhibits breast cancer cell growth. Our data show that Het-PyMT and Null-PyMT primary cells were much more sensitive for metformin treatment. Thus we examined the importance of AMPK signaling in our mouse models. Interestingly, both tumor tissues and primary cells derived from Null-PyMT breast tumors had lower AMPK activity. Together, our data strongly support that Nischarin disruption promotes breast tumor development and AMPK signaling is important for Nischarin-mediated suppression of breast tumor. Citation Format: Shengli Dong, Suresh K. Alahari. Nischarin disruption promotes breast tumor development in mouse models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3681.