Our objective is to establish the molecular basis for the contribution of the MUC1 mucin to tumorigenesis and metastasis. MUC1 is a cell associated mucin glycoprotein that is highly overexpressed in greater than 90 percent of carcinomas and metastatic lesions. We showed that spontaneous mammary gland tumors in mice lacking Muc1 had highly significant decreases in tumor growth rate and metastasis. Our hypothesis is that MUC1 is a multi-functional protein with structural features that contribute to its ability to modulate tumor progression and metastasis. One structural feature is the rodlike, densely glycosylated extracellular domain that modulates the adhesiveness of tumor cells and their vulnerability to immune effector cells. The second structural feature is the tyrosine phosphorylated cytoplasmic tail domain that interacts with proteins involved in signal transduction and cytoskeletal reorganization. To test our hypothesis, in aim 1 we will overexpress the human MUC1 protein in mammary glands of mice, directly mimicking the phenotype of MUC1 overexpression in human breast cancer. Development in the normal glands will be studied. These mice will be crossed with MMTV-MTag and MMTV-c-neu mice that develop spontaneous breast cancer and the bitransgenics will be examined for the effects of MUC1 overexpression. We will monitor tumor progression and metastasis. 2) To examine the functional significance of the MUC1 domains, we will overexpress MUC1 in transgenic mice with various domains deleted (tandem repeats, extracellular, and cytoplasmic domains) in normal glands and tumors to test the functions of these regions in tumorigenesis and development. 3) We will identify proteins interacting with MUC1 using the yeast two-hybrid technique and coimmunoprecipitation experiments and characterize the molecular details and consequences of MUC1 interactions with cytoplasmic proteins involved in signal transduction and cytoskeletal organization. The planned experiments will add to our understanding of how MUC1 modulates tumor progression and metastasis by virtue of its rodlike extracellular domains as well as through interactions of the cytoplasmic domain with proteins that are involved in signal transduction.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA064389-07
Application #
6172456
Study Section
Pathology B Study Section (PTHB)
Program Officer
Woodhouse, Elizabeth
Project Start
1994-07-01
Project End
2004-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
7
Fiscal Year
2000
Total Cost
$312,457
Indirect Cost
Name
Mayo Clinic, Arizona
Department
Type
DUNS #
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

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