The objectives of this revised new application are to continue development and study of a mouse model system which may provide insight into three aspects of breast cancer. Specifically, the applicant will utilize the recently developed transgenic mammary gland approach in studies of the divergent roles of the two most prevalent EGF family members in breast cancer: transforming growth factor alpha (TGFa) and amphiregulin (AR). He will examine in detail the contrasting effects of these two growth factors on mammary epithelial apoptosis, immortalization, tumorigenesis, and genetic instability. In addition, the interaction of each growth factor will be examined with the myc oncogene. Myc is an oncogene which promotes tumorigenesis by synergistic interaction with survival-promoting growth factors. Amplification of myc has been associated with poor prognosis of breast cancer in postmenopausal women. The purpose of the application will be to first characterize effects of AR and TGFa on the Bcl-XL/Bax ratio to modulate epithelial apoptosis, on telomerase to prevent epithelial senescence, and on cyclin D1/cdk-4 to shorten the G1 phase of the cell cycle. Genetic instability will be studied with a series of techniques, including newly established spectral karyotyping and comparative genomic hybridization methods. Subsequent aims compare AR and TGFa for effects on mammary stem cells, and for interaction with the Bcl-XL and Bcl-SS genes and the Myc oncogene using a combined transgenic mammary gland - transgenic mouse approach. This application is expected to provide insight into differential mechanisms of two EGF family growth factors to induce hyperplasia, interact with pregnancy/lactation, and interact with an oncogene particularly relevant to postmenopausal breast cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Gallahan, Daniel L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Georgetown University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Calvo, A; Catena, R; Noble, M S et al. (2008) Identification of VEGF-regulated genes associated with increased lung metastatic potential: functional involvement of tenascin-C in tumor growth and lung metastasis. Oncogene 27:5373-84
Chepko, G; Slack, R; Carbott, D et al. (2005) Differential alteration of stem and other cell populations in ducts and lobules of TGFalpha and c-Myc transgenic mouse mammary epithelium. Tissue Cell 37:393-412
Jamerson, M Hunter; Johnson, Michael D; Dickson, Robert B (2004) Of mice and Myc: c-Myc and mammary tumorigenesis. J Mammary Gland Biol Neoplasia 9:27-37
Pei, Xu Fang; Noble, Marcia S; Davoli, Maria Antonietta et al. (2004) Explant-cell culture of primary mammary tumors from MMTV-c-Myc transgenic mice. In Vitro Cell Dev Biol Anim 40:14-21
Deb, Tushar B; Coticchia, Christine M; Dickson, Robert B (2004) Calmodulin-mediated activation of Akt regulates survival of c-Myc-overexpressing mouse mammary carcinoma cells. J Biol Chem 279:38903-11
Jamerson, M H; Johnson, M D; Korsmeyer, S J et al. (2004) Bax regulates c-Myc-induced mammary tumour apoptosis but not proliferation in MMTV-c-myc transgenic mice. Br J Cancer 91:1372-9
Blancato, J; Singh, B; Liu, A et al. (2004) Correlation of amplification and overexpression of the c-myc oncogene in high-grade breast cancer: FISH, in situ hybridisation and immunohistochemical analyses. Br J Cancer 90:1612-9
Ramljak, Danica; Coticchia, Christine M; Nishanian, Tagvor G et al. (2003) Epidermal growth factor inhibition of c-Myc-mediated apoptosis through Akt and Erk involves Bcl-xL upregulation in mammary epithelial cells. Exp Cell Res 287:397-410
Kang, Jung Y; Dolled-Filhart, Marisa; Ocal, Idris Tolgay et al. (2003) Tissue microarray analysis of hepatocyte growth factor/Met pathway components reveals a role for Met, matriptase, and hepatocyte growth factor activator inhibitor 1 in the progression of node-negative breast cancer. Cancer Res 63:1101-5
Liao, Dezhong Joshua; Dickson, Robert B (2003) Cell death in MMTV-c-myc transgenic mouse mammary tumors may not be typical apoptosis. Lab Invest 83:1437-49

Showing the most recent 10 out of 16 publications