Identifying ECM Mediators of Tumor Cell Dormancy
Abstract
Characterize the compositional and functional changes in mammary stroma that result from tamoxifen treatment. Approach and Results: 75 mature female Sprague Dawley rats were randomized into three groups of 25 each; Gp1 nulliparous control, and Gp 2 tamoxifen treated (0.5 mg/tamoxifen per kg body weight, s.c. injection for 30 days)and Gp 3 tamoxifen treated (1.0 mg tamoxifen dose). ECM was harvested from the mammary glands of Gps 1 & 3 for biochemical and functional characterizations. The ECM preparations have been subjected to LCMS and MALDI-TOF mass spec. Due to technical difficulties we have also developed two in vitro models to investigate the effects of tamoxifen on mammary stroma. ECM deposited by primary mammary fibroblasts isolated from control and tamoxifen treated rats,or primary control fibroblasts treated with tamoxifen in culture has been utilized for ECM proteomics method development. Optimized conditions demonstrate fibronectin (FN) is downregulated by tamoxifen, in vitro and in vivo; observations consistent with data demonstrating that FN is upregulated during with MEC proliferation and downregulated at times of MEC loss; suggesting that loss of FN may be integral to a tumor suppressive microenvironment. To investigate functional changes in ECM, MDA-MB-231 cells were pre-mixed with control matrix or matrix isolated from tamoxifen treated rats and orthotopically injected into nude mice. Tumor growth was reduced in mice injected with ECM isolated from tamoxifen treated rats, demonstrating that tamoxifen altered ECM in a manner consistent with tumor cell dormancy. This work fulfills the goals of the DOD CDMRP Breast Cancer Research Program by challenging existing paradigms asserting that the protective mechanism of action of tamoxifen is mediated exclusively through action on mammary epithelial or tumor cells. Finally, this work has the potential to identify ECM mediators of tumor cell dormancy and progression that can be targeted for drug development.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2009
- Accession Number
- ADA514015
Entities
People
- Pepper J Schedin
Organizations
- University of Colorado Health