Heide Ford Assistant Professor Obstetrics & Gynecology Ph.D., 1995, University of Rochester Campus Box 8309 Biomedical Research Tower (RC1-North), Room 5102 Ph: 303-724-3509 Fax: 303-724-3512 Heide.Ford@UCHSC.edu

Homeobox genes encode transcription factors that play a crucial role in development. During development, many changes take place that parallel those seen in cancers, including alterations in cell proliferation and differentiation, in cell death, neovascularization, cell motility, and in invasion of surrounding tissue. Genes involved in normal developmental processes may therefore contribute to tumorigenesis if misexpressed.

Our laboratory focuses on a specific family of homeobox genes, the Six family, that has been implicated in both normal development and in tumorigenesis. We have shown that the Six1 homeobox gene is overexpressed in 50% of primary breast cancers and 90% of metastatic lesions. Our past data demonstrate that Six1 overexpression can attenuate the DNA damage-induced G2 checkpoint, and we have recently discovered that Six1 additionally plays a role in S-phase. Several of the Six family members are involved in the proliferation that is a prerequisite to cell type specification during normal development. We are thus interested in examining how a gene involved in proliferation during development may be “hijacked” to utilize this function in an aberrant setting to perform tumor promoting functions later in life.

To understand the role of the Six family of homeobox genes in cell cycle control, mammary gland development, and breast tumorigenesis, our laboratory uses numerous cutting edge technologies. These include cellular and molecular biology techniques such as microarray analysis, fluorescence in situ hybridization analysis, chromatin immunoprecipitations, and cell culture experiments, combined with transgenic and knockout mouse models to understand the in vivo roles of the Six family members in development and tumorigenesis.

Selected Publications

Behbakht K, Qamar L, Aldridge CS, Coletta RD, Davidson SA, Thorburn A, Ford HL Six1 overexpression in ovarian carcinoma causes resistance to TRAIL-mediated apoptosis and is associated with poor survival. Cancer Res. 2007 Apr 1;67(7):3036-42.

Christensen, K.L., Brennan, J.D.G., Aldridge, C.S. and Ford, H.L. Cell cycle regulation of the human Six1 homeoprotein is mediated by APC Cdh1. Oncogene. 2007 May 17;26(23):3406-14.

Coletta, R.D., Christensen, K., Lamb, J., Micomonaco, D., Huang, L., Wolf, D., Muller-Tidow, C., Golub, T.R., and Ford, H.L. (2004). The Six1 homeoprotein stimulates tumorigenesis by reactivation of the cyclin A1. Proc. Natl. Acad. Sci. USA 101: 6478-6483.

Reichenberger, K.J., Coletta, R.D., Schulte, A.P., Varella-Garcia, M. and Ford, H.L. (2005). Gene Amplification is a mechanism of Six1 overexpression in breast cancer. Cancer Res. 2005 Apr 1;65(7):2668-75.

Lamb, J., Ramaswamy, S., Ford, H.L., Contreras, B., Martinez, R.V., Kittrell, F.S., Zahnow, C.A., Patterson, N., Golub, T.R., and Ewen, M. E. (2003) A mechanism of cyclin D1 action encoded in the patterns of gene expression in human cancer. Cell 114: 323-334.

Geng, Y., Yu, Q., Whoriskey, W., Dick, F., Tsai, K., Ford, H.L., Biswas, D.K., Amati, B., Jacks, T., Richardson, A., Dyson, N., and Sicinski, P. (2001) Expression of cyclins E1 and E2 during mouse development and in oncogenesis. Proc. Natl. Acad. Sci. USA 98: 13138-13143.

Ford, H.L., Landesman-Bollag, E., Dacwag, C.S., Stukenberg, P.T., Pardee, A.B., Seldin, D. (2000) Cell Cycle Regulated Phosphorylation of the Human SIX1 Homeodomain Protein. J. Biol. Chem. 275, 22245-22254.

Guan, R.L., Ford, H.L., Fu, Y., Li, Y., Shaw, L.M., Pardee, A.B. (2000) Drg-1 as a Differentiation-Related, Putative Metastatic Suppressor Gene in Human Colon Cancer. Cancer Research. 60, 749-755.

Ford, H.L., Kabingu, E.N., Mutter, G.L., Bump, E., and Pardee, A.B. (1998) Abrogation of the G2 Cell Cycle Checkpoint Associated with Overexpression of HSIX1: A Possible Mechanism of Breast Carcinogenesis. Proc. Natl. Acad. Sci. USA 95: 12608-12613.

Selected Book Chapters/Reviews:

Coletta, R.D., Jedlicka, P., Gutierrez-Hartmann A., Ford, H.L. (2004). Transcriptional Control of the Cell Cycle in Mammary Gland Development and Tumorigenesis. Journal of Mammary Gland Biology and Neoplasia 9, 39-54.

Ford, H.L., Sclafani, R.A., and Degregori, J. (2003). “Cell Cycle Regulatory Cascades” in Cell Cycle and Growth Control: Biomolecular Regulation and Cancer. In press, Wiley Publishers.

Ford, H.L., Biswas, D.K., Martin, K.J., and Pardee, A.B. (2003) Discovery of Expressed Genes by Differential Display and Their Applications.In: Perspectives in Gene Expression. Eaton Publishing /Biotechniques Press, One Research Drive, Suite 400A, Westboro, MA 01581-6-070, pp. 3-20.

Ford, H.L. and Pardee, A.B. (2002) Cell Cycle Checkpoints In: Encyclopedia for Molecular Medicine (ed. Biderman, A.), John Wiley & Sons, Inc., New York, pp. 720-722.

Ford, H.L. and Pardee, A.B. (1999) Cancer and the Cell Cycle. J. of Cellular Biochem. 75 (S32), 166-172.

Ford, H.L. (1998) Homeobox genes: A Link Between Development, Cell Cycle, and Cancer? Cell Biol. Int. 22, 397-400.

Latest Publications in PubMed