Associate Professor of Cell and Developmental Biology,
Weill Medical College of Cornell University

Wnt proteins constitute a large family of secreted proteins that act as extracellular signaling factors. They function in cell fate determination and patterning in embryogenesis, and in the regulation of cell growth and differentiation in a variety of organ systems. Wnt genes were first discovered as mammary oncogenes in the mouse, and aberrant activation of the Wnt signaling pathway is associated with precancerous conditions in other tissues. in the laboratory centers on the mechanism of action of Wnt proteins, the intracellular signaling pathway through which they act, their phenotypic effects on target cells, and their functions in normal development and tumorigenesis.

Candidate cell surface receptors for Wnt proteins have recently been identified and we are investigating their functions, focusing on those expressed in mammary cells. We are using soluble biologically active forms of Wnt proteins to characterize ligand-receptor interactions and to investigate the specificity of action of different members of the Wnt family. Intracellular signaling pathways activated by Wnt proteins are also under investigation. signals act via a novel pathway that leads to stabilization of beta-catenin, a signaling intermediate that also plays a structural role in cell-cell adhesive junctions.  In response to Wnt signals, beta-catenin accumulates in the cytoplasm and enters the nucleus, where it modulates the transcription of specific target genes. 

We have recently found that one of the genes upregulated by Wnt signaling in mammary cells encodes cyclooxygenase-2 (Cox2), an enzyme that plays an important role in tumorigenesis.  The availability of drugs that selectively inhibit Cox-2 makes this enzyme an attractive target for cancer chemoprevention strategies.  We are therefore evaluating the significance of Cox-2 in experimental models of breast cancer. Overexpression of WNT genes has been reported in both breast and colon cancer in humans, and there is growing evidence that downstream components of the Wnt signaling pathway are activated in many human cancers. For example, the tumor suppressor gene APC, which is mutated in the majority of colorectal cancers, encodes a negative modulator of intracellular Wnt signaling. In addition, mutations in the beta-catenin gene, resulting in elevated levels of beta-catenin protein, have been observed in cancers of many different tissues. 

These and other data suggest that Wnt signaling is of widespread significance for early stage cancer in several tissues. For this reason, we are investigating experimental strategies for antagonizing the harmful effects of Wnt signaling in cancer.Wnt proteins, receptors, signal transduction, b-catenin, growth control, breast cancer, colon cancer.

Howe, L.R., Subbaramaiah, K., Brown, A.M.C., and Dannenberg, A.J. (2001) Cyclooxygenase-2: a target for the prevention and treatment of breast cancer. Endocrine-Related Cancer 8, 97-114.

Howe, L.R., Crawford, H., Hassell, J.A., Dannenberg, A.J., and Brown, A.M.C. (2001) PEA3 is upregulated in response to Wnt-1 and regulates the Cyclooxygenase-2 promoter. J. Biol. Chem., 276, 20108-20115.

Brown, A.M.C. (2001) Wnt signaling in breast cancer: have we come full circle? Breast Cancer Research 3, 351-355.

Kuraguchi, M., Yang, K., Wong, E.,Avdievich, E., Fan, K., Kolodner, R.D., Lipkin, M., Brown, A.M.C., Kucherlapati, R., and Edelmann, W. (2001) The distinct spectra of tumor-associated Apc mutations in mismatch repair deficient Apc 1638N mice define the roles of Msh3 and Msh6 in DNA repair and intestinal tumorigenesis. Cancer Res. 61, 7934-7942.

You, Z., Saims, D., Chen, S., Zhang, Z., Guttridge D.C., Guan, K-L., MacDougald, O.A., Brown, A.M.C., Evan, G., Kitajewski J., Wang, C-Y. (2002) Wnt signaling promotes oncogenic transformation by inhibiting c-Myc-induced apoptosis. J. Cell. Biol., 157, 429-440.

Kucherlapati, M., Yang, K., Kuraguchi, M., Zhao, J., Lia, M., Heyer, J., Kane, M., Fan, K., Russell, R., Brown, A.M.C., Kneitz, B., Edelmann, W., Kolodner, R., Lipkin, M., Kucherlapati, R. (2002) Haplo-insufficiency of Flap endonuclease (Fen1) leads to rapid tumor progression. Proc. Natl. Acad. Sci. U.S.A., 99, 9924-9929.

Howe, L. R., Subbaramaiah, K., Patel, J., Masferrer, J. L., Deora, A., Hudis, C., Thaler, H. T., Muller, W. J., Du, B., Brown, A. M. C., and Dannenberg, A. J. (2002) Celecoxib, a selective cyclooxygenase-2 inhibitor, protects against HER-2/neu-induced breast cancer. Cancer Res, 62, 5405-5407.

Wong, E., Yang, K., Kuraguchi, M., Werling, U., Avdievich, A., Fan, K., Fazzari, M., Jin, B., Brown, A.M.C., Lipkin, M., and Edelmann, W. (2002) Mbd4 inactivation increases C→T transition mutations and promotes gastrointestinal tumor formation. Proc. Natl. Acad. Sci. ( U.S.A.), 99, 14937-14942.

Brennan, K.R., and Brown, A.M.C. (2003) Is there a role for Notch signaling in human breast cancer? Breast Cancer Res., 5, 69-75.

Howe, L.R., Watanabe, O., Leonard, J., and Brown, A.M.C. (2003) Twist is upregulated in response to Wnt1 and inhibits mouse mammary cell differentiation. Cancer Res., 63, 1906-1913.

Anakwe, K., Robson, L., Hadley, J., Buxton, P., Church, V., Allen, S., Hartmann, C., Harfe, B., Nohno, T., Brown, A.M.C., Evans, D.J.R., and Francis-West, P . (2003) Wnt signalling regulates myogenic differentiation in the developing avian wing. Development, 130, 3503-3514.

Howe, L.R., and Brown, A.M.C. (2004) Wnt signaling and breast cancer. Cancer Biol. Ther. 3, 36-41.

Brennan, K., Gonzalez-Sancho, J.M., Castelo-Soccio, L.A., Howe, L.R., and Brown, A.M.C. (2004) Truncated mutants of the putative Wnt receptor LRP6/Arrow can stabilize β-catenin independently of Frizzled proteins. Oncogene, 23, 4873-4884.

Morin, P.J., Medina, M. Semenov, M.V., Brown, A.M.C., and Kosik, K.S. (2004) Wnt-1 induces exon 15 splicing and expression of L-APP. Neurobiology of Disease, 16, 59-67.

González-Sancho, J.M., Brennan, K.R., Castelo-Soccio, L.A., and Brown, A.M.C. (2004) Wnt proteins induce Dishevelled phosphorylation via an LRP5/6-independent mechanism, irrespective of their ability to stabilize β-catenin. Mol. Cell Biol., 24, 4757-4768.

Brennan, K., and Brown, A.M.C. (2004) Wnt proteins in mammary development and cancer. J. Mamm. Gland Biol. Neoplasia, 9, 119-131.

Chesnutt, C., Burrus, L.W., Brown, A.M.C., and Niswander, L. (2004) Coordinate regulation of neural tube patterning and proliferation by TGFβ and WNT activity. Dev. Biol., 274, 334-347.