MUC1 is a tumor antigen that is overexpressed on most carcinomas, including greater than 90% of breast carcinomas. This cell associated mucin is highly O-glycosylated and expressed at low levels on normal secretory epithelial tissues. MUC1 expression is greatly increased and the cellular localization is altered in tumors and metastases, where it is found surrounding the entire cell. Although MUC1 does not possess kinase activity, the cytoplasmic tail interacts with multiple signaling and adhesion-regulating proteins. Among these proteins are EGFR, erbB2, 3, and 4, Protein Kinase C delta, c-src, GSK3beta, p120 ctn, beta-catenin, and Grb2. We hypothesize that MUC1 serves as an adaptor protein that brings together kinases, phosphatases, and other adaptor proteins to assemble a complex that leads to tumor formation, possibly by inducing mitogenesis, and/or changes in the adhesive state of the cell. Overexpression of MUC1 in the mouse mammary gland, to mimic what is seen in humans, resulted in stochastic tumor formation in 63% of mice. Ninety percent of tumors metastasized to the lung. No tumors were observed in wildtype mice or mice expressing MUC1 lacking the cytoplasmic tail, suggesting that the cytoplasmic tail is critical to the function. To further characterize the oncogenic function of MUC1 in the mammary gland and other epithelial tissues, we propose: 1) to determine the critical portions of the MUC1 protein involved in tumorigenesis and define down-stream signaling pathways, 2) to determine the role of specific tyrosines in the MUC1 cytoplasmic tail, 3) to characterize additional interactions of the cytoplasmic tail with signaling and tumor suppressor proteins, and 4) to determine if MUC1 is oncogenic in tissues other than the mammary gland. These studies will significantly increase our understanding of the importance of MUC1 function in epithelial tumors during transformation, growth, invasion and metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA064389-14
Application #
7218557
Study Section
Pathology B Study Section (PTHB)
Program Officer
Woodhouse, Elizabeth
Project Start
1994-07-01
Project End
2009-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
14
Fiscal Year
2007
Total Cost
$346,110
Indirect Cost
Name
Mayo Clinic, Arizona
Department
Type
DUNS #
153665211
City
Scottsdale
State
AZ
Country
United States
Zip Code
85259
Al-Bataineh, Mohammad M; Kinlough, Carol L; Poland, Paul A et al. (2016) Muc1 enhances the ?-catenin protective pathway during ischemia-reperfusion injury. Am J Physiol Renal Physiol 310:F569-79
Lakshminarayanan, Vani; Supekar, Nitin T; Wei, Jie et al. (2016) MUC1 Vaccines, Comprised of Glycosylated or Non-Glycosylated Peptides or Tumor-Derived MUC1, Can Circumvent Immunoediting to Control Tumor Growth in MUC1 Transgenic Mice. PLoS One 11:e0145920
Pastor-Soler, NĂºria M; Sutton, Timothy A; Mang, Henry E et al. (2015) Muc1 is protective during kidney ischemia-reperfusion injury. Am J Physiol Renal Physiol 308:F1452-62
Poh, Tze Wei; Madsen, Cathy S; Gorman, Jessica E et al. (2013) Downregulation of hematopoietic MUC1 during experimental colitis increases tumor-promoting myeloid-derived suppressor cells. Clin Cancer Res 19:5039-52
Finke, James H; Rayman, Pat A; Ko, Jennifer S et al. (2013) Modification of the tumor microenvironment as a novel target of renal cell carcinoma therapeutics. Cancer J 19:353-64
Ghosh, Subrata K; Uchida, Masashi; Yoo, Byunghee et al. (2013) Targeted imaging of breast tumor progression and therapeutic response in a human uMUC-1 expressing transgenic mouse model. Int J Cancer 132:1860-7
Roy, L D; Sahraei, M; Subramani, D B et al. (2011) MUC1 enhances invasiveness of pancreatic cancer cells by inducing epithelial to mesenchymal transition. Oncogene 30:1449-59
Petersson, J; Schreiber, O; Hansson, G C et al. (2011) Importance and regulation of the colonic mucus barrier in a mouse model of colitis. Am J Physiol Gastrointest Liver Physiol 300:G327-33
Kinlough, Carol L; Poland, Paul A; Gendler, Sandra J et al. (2011) Core-glycosylated mucin-like repeats from MUC1 are an apical targeting signal. J Biol Chem 286:39072-81
Poh, Tze Wei; Bradley, Judy M; Mukherjee, Pinku et al. (2009) Lack of Muc1-regulated beta-catenin stability results in aberrant expansion of CD11b+Gr1+ myeloid-derived suppressor cells from the bone marrow. Cancer Res 69:3554-62

Showing the most recent 10 out of 31 publications