The long-term objective of this proposal is to understand the role of caveolin-1 in mammary epithelial-stromal interactions, during mammary tumorigenesis (a.k.a., the tumor microenvironment). Here, we will investigate the development of epithelial cell hyperplasia in the mammary glands of Cav-1 null mice. More specifically, we will mechanistically dissect the individual contributions of epithelial or non-epithelial cells to this hyperplastic Cav-1 null phenotype. Using both in vitro and in vivo mammary reconstitution experiments, we will explore whether the specific loss of Cav-1 within mammary epithelial cells or non-epithelial cells (i.e. stromal cells, including fibroblasts and adipocytes) both contribute to a dysregulation of epithelial proliferation and tumorigenesis. The two Specific Aims (SAs) of the project are: SA1) To examine the role of Cav-1 in epithelial-stromal interactions during mammary tumorigenesis. For this purpose, we will explore whether the specific loss of Cav-1 within mammary epithelial cells or non-epithelial cells (i.e. stromal cells, including fibroblasts and adipocytes) both contribute to a dysregulation of epithelial cellular proliferation, hyperplasia, and tumorigenesis, using mammary reconstitution experiments. Additional studies will be carried out with human breast cancer samples to identify CAV-1 mutations in mammary stromal cells. SA2) To determine the effects of Cav-1 expression on Cyclin D1-induced mammary tumorigenesis. In this aim, we will evaluate how Cav-1 expression modulates Cyclin D1-induced mammary tumorigenesis, by crossing Cav-1 (-/-) null and Cav-1 transgenic (Tg) mice, with MMTV-Cyclin D1 transgenic mice. Complementary experiments will be carried out employing the therapeutic administration of a cell permeable caveolin-1-based mimetic peptide. In this context, epithelial-stromal contributions will also be evaluated. These studies will contribute fundamental knowledge toward understanding the role of Cav-1 in regulating epithelial-stromal interactions, during mammary cell transformation and tumorigenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA120876-04
Application #
7880060
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Mohla, Suresh
Project Start
2007-08-03
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
4
Fiscal Year
2010
Total Cost
$294,500
Indirect Cost
Name
Thomas Jefferson University
Department
Pathology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Ju, Xiaoming; Ertel, Adam; Casimiro, Mathew C et al. (2013) Novel oncogene-induced metastatic prostate cancer cell lines define human prostate cancer progression signatures. Cancer Res 73:978-89
Trimmer, Casey; Bonuccelli, Gloria; Katiyar, Sanjay et al. (2013) Cav1 suppresses tumor growth and metastasis in a murine model of cutaneous SCC through modulation of MAPK/AP-1 activation. Am J Pathol 182:992-1004
Capparelli, Claudia; Chiavarina, Barbara; Whitaker-Menezes, Diana et al. (2012) CDK inhibitors (p16/p19/p21) induce senescence and autophagy in cancer-associated fibroblasts, ""fueling"" tumor growth via paracrine interactions, without an increase in neo-angiogenesis. Cell Cycle 11:3599-610
Carito, Valentina; Bonuccelli, Gloria; Martinez-Outschoorn, Ubaldo E et al. (2012) Metabolic remodeling of the tumor microenvironment: migration stimulating factor (MSF) reprograms myofibroblasts toward lactate production, fueling anabolic tumor growth. Cell Cycle 11:3403-14
Guido, Carmela; Whitaker-Menezes, Diana; Lin, Zhao et al. (2012) Mitochondrial fission induces glycolytic reprogramming in cancer-associated myofibroblasts, driving stromal lactate production, and early tumor growth. Oncotarget 3:798-810
Sotgia, Federica; Martinez-Outschoorn, Ubaldo E; Howell, Anthony et al. (2012) Caveolin-1 and cancer metabolism in the tumor microenvironment: markers, models, and mechanisms. Annu Rev Pathol 7:423-67
Chiavarina, Barbara; Martinez-Outschoorn, Ubaldo E; Whitaker-Menezes, Diana et al. (2012) Metabolic reprogramming and two-compartment tumor metabolism: opposing role(s) of HIF1? and HIF2? in tumor-associated fibroblasts and human breast cancer cells. Cell Cycle 11:3280-9
Capparelli, Claudia; Guido, Carmela; Whitaker-Menezes, Diana et al. (2012) Autophagy and senescence in cancer-associated fibroblasts metabolically supports tumor growth and metastasis via glycolysis and ketone production. Cell Cycle 11:2285-302
Capparelli, Claudia; Whitaker-Menezes, Diana; Guido, Carmela et al. (2012) CTGF drives autophagy, glycolysis and senescence in cancer-associated fibroblasts via HIF1 activation, metabolically promoting tumor growth. Cell Cycle 11:2272-84
Katiyar, Sanjay; Jiao, Xuanmao; Addya, Sankar et al. (2012) Mammary gland selective excision of c-jun identifies its role in mRNA splicing. Cancer Res 72:1023-34

Showing the most recent 10 out of 83 publications