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Ford Lab


Phone:     (303) 724-3509





Research Interests:

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-b 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. 
Selected Publications
1.  Micalizzi, D.S., Wang, C., Schiemann, W. P., Ford, H.L. (2010).  The Six1 Homeoprotein Increases the Level of the TGF-b Type I Receptor and Converts TGF-b Signaling from Tumor Suppressive to Tumor  Promotional. Cancer Research 70: 10371-80. 


2. Menke, C., Bin, L., Thorburn, J., Behbakht, K., Ford, H.L., and Thorburn, A. (2011). TRAIL resistance mechanisms can be overcome by proteasome inhibition but not generally by synergizing agents. Cancer  Research 71: 1883-1892. 


3. Menke, C., Gonchararov, T., Qamar, L., Korch, C., Ford, H.L., Behbakht, K., Thorburn, A. (2011). TRAIL receptor signaling regulates chemosensitivity in vivo. PLoS ONE 6: 14527.


4.   Farabaugh, S.M., Micalizzi, D.S., Jedlicka, P., Zhao, R., and Ford, H.L. (2012). Eya2 Is Required to Mediate the Pro-Metastatic Functions of Six1 Via the Induction of TGF-β Signaling, Epithelial- Mesenchymal Transition, and Cancer Stem Cell Properties. Oncogene 31: 552-562.

5.  Wang, C., Jedlicka, P., Patrick, A.N., Micalizzi, D.S., Lemmer, K.C., Deitsch, E., Casas-Selves, M., Harrell, J.C., Ford, H.L. (2012).  A novel pro-lymphangiogenic Six1-VEGF-C pathway mediates breast cancer metastasis.  Journal of Clinical Investigation 122: 1895-1906. *Associated commentary by McCarthy, N. in Nature Cancer Reviews 12: 316.  “Metastasis: SIX1 of the best”.


6.  Smith, A.L., Iwanaga, R., Drasin, D.J., Micalizzi, D.S., Vartuli, R.L., Tan, A-C., and Ford, H.L. (2012).  The miR106b-25 cluster targets Smad7, activates TGF-b signaling, and induces EMT and tumor   initiating cell characteristics downstream of Six1 in human breast cancer.  Oncogene 13: 5162-5171. 


7.  Iwanaga, R., Wang, C., Micalizzi, D.S., J.C. Harrell, Jedlicka, P., Sartorius, C., Kabos, P., Farabaugh, S., Bradford, A., Ford, H.L. (2012). The Six1 Expression of Six1 in luminal breast cancers predicts poor    prognosis and promotes increases in tumor initiating cells by activation of ERK and TGF-b pathways. Breast Cancer Res 14: R100 (e-pub ahead of print July 5, 2012)


8.  Robin, T., Smith, A.L., McKinsey, R., Reaves, L., Jedlicka*, P., Ford, H.L.* (2012).  EWS/Fli1 regulates Eya3 in Ewing’s sarcoma cells via modulation of microRNAs 145 and 708, resulting in increased survival and chemoresistance. Molecular Cancer Research 10: 1098-1108. *co-corresponding authors


9. Krueger, A.B., Dehdashti, S.J., Southall, N., Marugan, J.J., Ferrer, M., Li, X., Ford, H.L., Zheng, W.*, and  Zhao, R.*.  (2012) High throughput screening identifies a class of specific Eya2 phosphatase inhibitors.  Journal of Biomolecular Screening 18: 85-96. *co-corresponding authors. (e-pub ahead of print July 20, 2012)


10.  Patrick, A.N., Cabrera, J.H., Smith, A.L., Chen, X.S., Ford, H.L.*, and Zhao, R.* (2013).  Structure-   Function Analyses of the SIX1-EYA2 Complex Reveals Insights into Metastasis and BOR Syndrome.  Nature Structural & Molecular Biology 20: 447-453.  *co-corresponding   authors.11.  Auvergne, R.M., Sim, F.R., Wang, S., Chandler-Militello D.,  Burch, J., Al Fanek, Y., Davis, D.,  Benraiss, A., Walter, K., Achanta, P., Johnson, M., Quinones-Hinojosa, A., Natesan, S., Ford, H.L., Goldman,   S.A. (2013).  Cell Reports.  In press, e-pub ahead of print May 29, 2013.

Reviews (new since 2010):

1.  Micalizzi, D.S., Farabaugh, S., and Ford, H.L. (2010).  Epithelial-Mesenchymal Transition in Cancer:  Parallels between Normal Development and Tumor Progression.  J of Mammary Gland Biology and Neoplasia 15: 117-134.


2.  Ford, H.L. and Thompson, E.W. (2010). Mammary gland studies as important contributors to the cause  of epithelial mesenchymal plasticity in malignancy. J of Mammary Gland Biology and Neoplasia 15:  113-115.


3.  Drasin, D.J., Robin, T.P., and Ford, H.L. (2011). Breast cancer epithelial-to-mesenchymal transition: examining the functional consequences of plasticity. Breast Cancer Research 13: 226.


4.  Dimberg, L.Y., Anderson, C.K., Camidge, R., Behbakht, K., Thorburn, A., Ford, H.L. (2012). On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics.  In press, Oncogene (e-pub ahead of print, May 14).


5.  Smith, A.L., Robin, T, Ford, H.L. (2012) Molecular Pathways: Targeting the TGF-β Pathway for Cancer        Therapy.  Clinical Cancer Research 18: 4514-21.


6.  Powell, D.R.*, O’Brien, J.H.*, Ford, H.L., Artinger, K.B. Chapter 17: Neural crest cells and cancer:   insights into tumor progression, in Neural Crest, P. Trainor, (Ed.), San Diego: Elsevier, in press.

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