CAV-1, StatSa Signaling, and Estrogen-Dependent Breast Cancer The human Caveolin-1 (Cav-1) gene acts as a mammary gland tumor suppressor. We have previously identified Cav-1 inactivating (dominant-negative (DN)) mutations in up to 35 % of estrogen receptor (ER) positive breast cancer patients. Our hypothesis is that up-regulation of ER levels and activity are caused by Cav-1 inactivating mutations. As Cav-1 functions as an inhibitor of the Jak-2 kinase, we propose that StatSa activation is the mechanism by which loss of Cav-1 function results in increased ER-alpha levels. In support of this hypothesis, we present novel evidence that StatSa activation is sufficient to upregulate ER-alpha levels in ER-negative human breast cancer cells. As such, our preliminary studies have now defined a novel signaling pathway leading to breast cancer: Cav-1 gene inactivation (DN-mutations) -->StatSa activation --> ER-alpha upreoulation ->Cvclin D1 over-expression. The three Specific Aims of the project are: 1) Determine the role of StatSa activation and ER-alpha in Cav-1-related mammary hyperplasia. proliferation, and 3D lumen formation. We will analyze the mammary glands of Cav-1/StatSa double- knockout mice and study the ex vivo behavior of primary cultures of mammary epithelia from these mice. 2) Determine the role of StatSa activation and ER-alpha in Cav-1-related mammary tumorigenesis and metastasis. For this purpose, we will perform orthotopic transplantation of Met-1 cells expressing Cav-1 dominant-negative (DN) mutants (such as P132L) that are found in human breast cancer. The role of StatSa signaling will be assessed using DN mutants of StatSa and Jak-2. The role of estrogen will be assessed by ovariectomy and supplementation with estrogen pellets. Tamoxifen-resistance will also be investigated. 3) Determine if Cav-1 mutations co-segregate with StatSa activation in ER(+) human breast cancer samples. Here, we propose to examine the relevance of this newly defined signaling pathway in human breast cancer pathogenesis, using Cav-1 mutations, ER-alpha expression levels, and StatSa activation as novel prognostic markers. Since greater than 40% of ER-apha positive patients show tamoxifen-resistance, we will also examine if Cav-1 mutations and StatSa activation are critical predictors of tamoxifen-resistance.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA098779-11
Application #
8206585
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Mohla, Suresh
Project Start
2003-01-23
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
11
Fiscal Year
2012
Total Cost
$325,655
Indirect Cost
$114,875
Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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Capozza, Franco; Trimmer, Casey; Castello-Cros, Remedios et al. (2012) Genetic ablation of Cav1 differentially affects melanoma tumor growth and metastasis in mice: role of Cav1 in Shh heterotypic signaling and transendothelial migration. Cancer Res 72:2262-74
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Pavlides, Stephanos; Vera, Iset; Gandara, Ricardo et al. (2012) Warburg meets autophagy: cancer-associated fibroblasts accelerate tumor growth and metastasis via oxidative stress, mitophagy, and aerobic glycolysis. Antioxid Redox Signal 16:1264-84
Salem, Ahmed F; Bonuccelli, Gloria; Bevilacqua, Generoso et al. (2011) Caveolin-1 promotes pancreatic cancer cell differentiation and restores membranous E-cadherin via suppression of the epithelial-mesenchymal transition. Cell Cycle 10:3692-700
Balliet, Renee M; Capparelli, Claudia; Guido, Carmela et al. (2011) Mitochondrial oxidative stress in cancer-associated fibroblasts drives lactate production, promoting breast cancer tumor growth: understanding the aging and cancer connection. Cell Cycle 10:4065-73
Sotgia, Federica; Martinez-Outschoorn, Ubaldo E; Pavlides, Stephanos et al. (2011) Understanding the Warburg effect and the prognostic value of stromal caveolin-1 as a marker of a lethal tumor microenvironment. Breast Cancer Res 13:213

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