The objective of this proposal is to understand the role of mammary adipocytes and adipocyte-secreted factors (such as, Type-VI collagen): i) in the growth/survival of mammary epithelial cells; and ii) in the pathogenesis of breast cancer. Mammary epithelial cells/ducts are embedded in a matrix that consists predominantly of adipocytes. However, it remains unknown what adipocyte-secreted factors are required for the survival of mammary epithelia. Similarly, these unknown adipocyte-specific factors may contribute to the pathogenesis of human breast cancers. To test this hypothesis, we will use a variety of novel in vivo approaches, such as """"""""reconstituted mammary fat pads (RFPs)"""""""" employing the transfectable 3T3-L1 model adipocyte cell line, and Type-VI collagen (-/-) null mice. The three specific aims of the project are: 1) To identify paracrine interactions between mammary epithelia and their surrounding adipocytes. We will establish co-culture and conditioned media systems using 3T3-L1 adipocytes and the human breast cancer epithelial cell line, MCF-7. We will use microarray analysis to define adipocyte-induced transcriptional changes in MCF-7 and thereby identify genes that mediate the growth and survival of MCF-7 cells. To functionally examine the role of specific factors, we will generate """"""""reconstituted fat pads (RFPs)"""""""" using stably-transfected 3T3-L1 adipocytes over-expressing a given gene product. These RFPs will be co-implanted with MCF-7 cells into nude mice to assess their contribution to tumorigenicity in vivo; 2) To determine the role of Type-VI collagen in mammary tumorigenesis. Our preliminary data demonstrate that Type-VI collagen is an abundant extracellular matrix component of mammary tissue that is secreted by adipocytes and that is up-regulated during mammary tumor progression. We will cross Type-VI collagen null mice with an established mouse model of mammary tumorigenesis, MMTV-ErbB2/Neu. We predict that loss of Type-VI collagen expression will block or diminish the development of mammary tumors; and 3) To determine if selective ablation of mammary adipocytes in the adult mouse prevents or diminishes mammary tumor development. For this purpose, we have developed a novel transgenic inducible system that allows the selective apoptotic ablation of mammary adipocytes, in a temporally controlled fashion that will be crossed to MMTV-PyMT mice. In a complementary approach, we will induce the selective-ablation of mammary epithelial cells. We have placed a ligand-activatable transgenic cassette containing pro-caspase-8 under the control of the aP2-promoter (for expression in adipocytes) and the MMTV-promoter (for expression in mammary epithelia). These studies will help define the role of mammary adipocytes in the pathogenesis of breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA112023-01A1
Application #
6970443
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Mohla, Suresh
Project Start
2005-06-01
Project End
2010-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
1
Fiscal Year
2005
Total Cost
$325,710
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
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