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Heide L. Ford, Associate Professor

Ph.D. (1995) University of Rochester




Associate Professor, Deptartment of Pharmacology
Director, Biomedical Sciences Program
Co-Director, Hormone Related Malignancies, UCCC


Campus Box 8309
RC1-North, P18-6115
Phone: 303-724-3509
Fax: 303-724-3663

Heide.Ford@UCDenver.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 and/or metastasis if misexpressed. In addition, because many homeobox genes are embryonic genes with little to no expression in adult tissues, inhibitors of their expression/activity may significantly inhibit cancer while conferring limited side effects.

Our laboratory focuses on a specific family of homeoproteins, the Six family, and their transcriptional cofactors, Eya and Dach. The Six1 homeobox gene is overexpressed in 50% of primary breast cancers and 90% of metastatic lesions, and its overexpression correlates with poor prognosis in multiple tumor types, including breast, ovarian, prostate, colon, and brain, as well as the pediatric tumor rhabdomyosarcoma. Our past data demonstrate that Six1 overexpression can attenuate the DNA damage-induced G2 checkpoint and that it can also increase overall cellular proliferation. In addition, we have found that Six1 inhibits certain forms of apoptosis. Several of the Six family members are involved in the proliferation and survival of progenitor cell populations during normal development, and thus, when misexpressed in adult tissues, these genes may lead to the expansion of a tumor initiating, or stem cell population, thereby contributing to uncontrolled growth and tumorigenesis.

Additional developmental roles for the Six/Eya transcriptional complex include the promotion of migration and invasion, properties that are also important for the metastatic dissemination of tumor cells. Using animal models we have recently shown that Six1 can promote both tumor initiation and metastasis. We are currently focusing much of our attention on the mechanism by which the Six1/Eya transcriptional complex can induce metastatic dissemination, with a specific emphasis on its ability to induce an epithelial to mesenchymal transition (EMT) and an induction of cancer stem cells, largely through activation of the TGF-β signaling pathway. We are examining how Six1 induces such phenotypes by identifying both miRNA and gene targets of the Six1 transcription factor. Because we have shown that Six1 can induce both tumor onset and metastasis, and because its expression correlates with poor prognosis in many human tumors, we are performing X-ray crystallography as well as high throughput screening (HTS) in an effort to combine rational-based drug design with more typically used HTS mechanisms to identify small molecule inhibitors of the complex. Thus, we are interested not only in examining the mechanism by which developmental genes may be "hijacked" in tumors to promote proliferation, survival, migration, and invasion, but are also interested in identifying novel drugs to inhibit these developmental molecules as anti-cancer therapies.

To understand the role of the Six/Eya/Dach transcriptional network in tumorigenesis and metastasis, our laboratory uses numerous cutting edge technologies. These include cellular and molecular biology techniques such as microarray analysis and siRNA screens, miRNA analysis, fluorescence in situ hybridization analysis, chromatin immunoprecipitations, deep sequencing, X-ray crystallography, cell culture experiments, as well as the use of xenograft, transgenic, and knockout mouse models.

Coletta, R.D., McCoy, E.L., Burns, V., Kawakami, K., McManaman, J.L., Wysolmerski, J.J., and Ford,H.L. (2010). Characterization of the Six1 Homeobox Gene in Normal Mammary Gland Morphogenesis. BMC Developmental Biology 10(1): 4.

McCoy, E.L., Iwanaga, R., Jedlicka, P., Abbey. N-S., Chodosh, L.A., Heichman, K., Welm, A.L., and Ford, H.L. (2009). Six1 Expands the Mouse Mammary Epithelial Stem/Progenitor Cell Pool and Induces Mammary Tumors that Undergo Epithelial-Mesenchymal Transition. Journal of Clinical Investigation 119: 2663-2677.
*Associated commentary “Defining a role for the homeoprotein Six1 in EMT and mammary tumorigenesis” by D. Radisky. Journal of Clinical Investigation 119: 2528-2531.

Micalizzi, D.S., Christensen, K.L., Jedlicka, P., Coletta, R.D., Baron, A.E., Harrell, J.C., Horwitz, K., Billheimer, D., Heichman, K., Welm, A., Schiemann, W.B., and Ford, H.L. (2009). The Six1 Homeoprotein Induces Human Mammary Carcinoma Cells to Undergo Epithelial-Mesenchymal-Transition and Metastasis in Mice through Increasing TGF-β Signaling. Journal of Clinical Investigation 119: 2678-2690.
*Associated commentary “Defining a role for the homeoprotein Six1 in EMT and mammary tumorigenesis” by D. Radisky. Journal of Clinical Investigation 119: 2528-2531.

Patrick, A.N., Schiemann, B.J., Yang, K., Zhao, R.*, and Ford, H.L.* (2009). Biochemical and Functional Characterization of 6 Six1 Branchio-Oto-Renal Syndrome Mutations. Journal of Biological Chemistry 284(31): 20781-90. *co-corresponding authors.

McCoy, E.L., Kawakami, K., and Ford, H.L., and Coletta, R.D. (2009). Expression of Six1 homeobox gene during development of the mouse submandibular salivary gland. Oral Diseases 15: 407-413.

Coletta, R.D., Christensen, K., Micalizzi, D.S., Varella-Garcia, M., Jedlicka, P., and Ford, H.L. (2008). Six1 overexpression in mammary cells induces genomic instability and is sufficient for malignant transformation. Cancer Research 68: 2204-2213

Behbakht, K., Qamar, L., Aldridge, C., Coletta, R.D., Davidson, S., Thorburn, A., and Ford, H.L. (2007). Six1 overexpression in ovarian cancers causes resistance to TRAIL-mediated apoptosis and is associated with poor survival. Cancer Research 67: 3036-3042.

Christensen, K., Brennan, J.D.G., Aldridge, C. and Ford, H.L. (2007). Cell Cycle Regulation of Human Six1 is Mediated by APC-Cdh1 through a Novel Signal Sequence. Oncogene 26: 3406-3414.

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 Research 65: 2668-2675.

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.

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. Journal of Biological Chemistry 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:

Micalizzi, D.M. and Ford, H.L. (2009). EMT in Development and Cancer. Future Oncology 5: 1129-1143.

Christensen, K.L., Patrick, A.N., McCoy, E.L. and H.L. Ford (2008). The Six family of homeobox genes in development and Cancer. Advances in Cancer Research 101:93-126.

Thorburn, A., Behbakht, K., and Ford, H.L. (2008). “TRAIL Receptor-targeted therapeutics: Resistance mechanisms and strategies to avoid them.” Drug Resistance Updates 11; 17-24.

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. (2004). “Cell Cycle Regulatory Cascades” in Cell Cycle and Growth Control: Biomolecular Regulation and Cancer. Wiley & Sons, Inc., Hoboken, New Jersey, p95.

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. Journal of Cellular Biochemistry 75 (S32), 166-172.

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


Latest Publications in PubMed