The APC tumor suppressor:  a critical regulator of development and neoplasia of the intestine and mammary gland

Inactivation of the APC tumor suppressor is a common and early event in human colorectal cancer and has been identified in breast cancer, among other tumor types.  Mouse studies indicate that APC is required to maintain intestinal and mammary epithelial cell homeostasis, and its loss results in tumorigenesis in these tissues.  Our overall objective is to identify the mechanism by which APC acts as a tumor suppressor in intestinal and mammary epithelial cells using both in vitro and in vivo approaches.  Based on data from our laboratory and others, we are testing the working hypothesis that APC mediates epithelial cell polarity and survival in the mammary gland and intestine through mechanisms that do not involve ß-catenin-mediated gene regulation.   Specific ongoing projects in the laboratory include 1) manipulation of APC expression in non-transformed epithelial cells and cancer cells, 2) identification of APC-mediated effects in epithelial cells that are ß-catenin-dependent and –independent, and 3) characterization of defective mammary alveolar development in Apc-mutant mice.  In the long term, this work will contribute to the overall understanding of the APC/ß-catenin pathway in development and tumorigenesis and perhaps facilitate the design of novel therapeutic approaches to target this pathway in human cancers.

Heppner Goss, K., Trzepacz, C., Tuohy, T.M.F. and Groden, J.  Attenuated APC alleles produce functional protein from internal translational initiation.  Proc. Natl. Acad. Sci. USA,  99, 8161-8166, 2002.

Heinen, C.D., Goss, K.H., Cornelius, J., Babcock, G.F., Knudsen, E.S., Kowalik, T. and Groden, J. The APC tumor suppressor controls entry into S-phase through its ability to regulate the cyclin D/RB pathway.  Gastroenterology. 123, 751-763, 2002.

Goss, K.H., Risinger, M., Kordich, J., Sanz, M.M., Straughen, J.E., Slovek, L.E., Capobianco, A.J., German, J., Boivin, G.P. and Groden, J.  Enhanced tumor formation in mice heterozygous for Blm mutation. Science, 297, 2051-2053, 2002.

Reichling, T.D., Goss, K.H., Carson, D.J., Ley-Ebert, C., Witte, D., Aronow, B. and Groden, J. Transcriptional profiles of intestinal tumors in ApcMin/+ mice are unique from those of embryonic intestine and identify novel gene targets dysregulated in human colorectal tumors.  Cancer Res., 65, 166-176, 2005.

Mak, G.Z., Kavanaugh, G.M., Buschmann, M.M., Stickley, S.M., Koch, M., Goss, K.H., Waechter, H., Zuk, A. and Matlin, K.S. Regulated synthesis and functions of Laminin 5 in polarized Madin-Darby Canine Kidney (MDCK) epithelial cells. Mol. Biol. Cell., 17, 3664-3677, 2006.