Abstract

Breast carcinoma is the most common form of cancer in women in the United States. Understanding the basic molecular markers during the transitions from normal cell to carcinoma to metastases will be helpful in treating the disease, but these processes still are poorly understood. Tumors arise from individual cells that undergo multiple genomic mutations. How do the initial mutations arise? Does the environment cause mutations or create an environment that promotes their accumulation? Extracellular matrix proteins, such as matrix metalloproteinases (MMPs), contribute to tumor progression. MMP-3/Stromelysin-1 has been shown to be involved in promoting mammary hyperplasia and cancer in mice; it is upregulated in human breast cancer, and its overexpression promotes genomic instability. In the research proposed, I will address the mechanism of genomic instability in cancer progression.
The specific aims to be covered in this proposal are the following: (1) Examine the effect of MMP-3 on mammary stem cell differentiation. Recent work suggests that progenitor cells may be tumor precursors. (2) Determine if MMP-3 affects the rate of mutagenesis in mammary tumor development. (3) Examine effect of apoptosis on generating genomic instability and on MMP-3-dependent mammary tumor progression.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA103534-03
Application #
6952366
Study Section
Special Emphasis Panel (ZRG1-F09 (20))
Program Officer
Lohrey, Nancy
Project Start
2003-07-23
Project End
2006-07-22
Budget Start
2005-07-23
Budget End
2006-07-22
Support Year
3
Fiscal Year
2005
Total Cost
$48,296
Indirect Cost

  Institution

Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143

  Publications

Littlepage, Laurie E; Adler, Adam S; Kouros-Mehr, Hosein et al. (2012) The transcription factor ZNF217 is a prognostic biomarker and therapeutic target during breast cancer progression. Cancer Discov 2:638-51
Littlepage, Laurie E; Sternlicht, Mark D; Rougier, Nathalie et al. (2010) Matrix metalloproteinases contribute distinct roles in neuroendocrine prostate carcinogenesis, metastasis, and angiogenesis progression. Cancer Res 70:2224-34
Adler, Adam S; Littlepage, Laurie E; Lin, Meihong et al. (2008) CSN5 isopeptidase activity links COP9 signalosome activation to breast cancer progression. Cancer Res 68:506-15
Egeblad, M; Littlepage, L E; Werb, Z (2005) The fibroblastic coconspirator in cancer progression. Cold Spring Harb Symp Quant Biol 70:383-8