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 44% 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
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. In press Cancer Research.
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.
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