Louise R. Howe, Ph.D.
Mammary Tumorigenesis Laboratory

Head, Mammary Tumorigenesis Laboratory, Strang Cancer Prevention Center
Assistant Professor of Cell & Developmental Biology, Weill Medical College of Cornell University

We are interested in understanding the molecular mechanisms that underlie the development and growth of breast cancer, and thus identifying molecular targets for chemopreventive or therapeutic intervention. Our approach utilizes a combination of cell biology, molecular biology and whole animal techniques. We use a variety of transgenic mouse models, including HER2/Neu transgenic strains and Wnt1 transgenic mice, which provide highly relevant models of human breast cancer. These strains develop mammary adenocarcinomas due to mammary-targeted expression of HER2/neu and Wnt1 oncogenes, respectively.

The HER2/neu gene is overexpressed in 20-30% of human breast cancers, and is associated with poor patient prognosis, providing significant impetus for the development of targeted therapies. HER2/neu encodes a cell-surface growth factor receptor with intrinsic tyrosine kinase activity, and HER2/neu signaling stimulates a pathway involving p21ras and MAP kinase activation. One goal of our research is to identify components of this signaling pathway that may be useful therapeutic or preventive targets.

The Wnt/ß-catenin pathway offers another potentially useful source of targetable molecules. Wnt1 and several other Wnt family members stimulate accumulation of ß-catenin protein, which then induces transcriptional activation of numerous genes via interaction with transcription factors of the TCF/Lef family. This Wnt/ß-catenin signaling pathway is activated in multiple human cancers, predominantly by mutation of components of the pathway. A hallmark of Wnt signaling is aberrant cytoplasmic and nuclear accumulation of ß-catenin protein, which can be detected immunohistochemically in cancer tissues. In particular, the pathway is activated in ~95% of human colorectal cancers due to mutations in the APC tumor suppressor gene, or less commonly in the ß-catenin gene itself. Interestingly, nucleocytoplasmic ß-catenin has been observed in ~60% of human breast carcinomas, demonstrating that the Wnt/ß-catenin pathway is active in the majority of breast cancers, although the activating mutation(s) have yet to be identified. Nevertheless, it is clear that identification of genes transcriptionally activated in response to Wnt signaling will be important for providing therapeutic targets with widespread relevance to human cancer, and particular relevance to breast cancer.

In collaboration with Dr. Andrew Dannenberg at Weill-Cornell Medical College, we have identified the inducible prostaglandin synthase cyclooxygenase-2 (COX-2) as a target of both HER2/neu and Wnt signaling. COX-2 was initially identified as an anti-cancer target in the context of colorectal neoplasia. However, it is now apparent that COX-2 is also overexpressed in about 40% of human breast cancers, particularly in those which overexpress HER2/neu. We have shown that HER2/neu-induced breast cancer can be prevented using both pharmacological and genetic approaches in mouse models. Thus, HER2/neu-induced mammary neoplasia can be reduced by knocking out the COX-2 gene or by administering a selective COX-2 inhibitor. Together these observations provide important proof-of-principle data to support further investigation into inhibiting the COX/PG pathway as a useful anti-breast cancer strategy.

Additionally, we are studying the mechanisms by which genes are upregulated in response to mammary oncogenes such as HER2/neu and Wnt1. We have found that several relevant genes, including COX-2 and Twist, are activated by the PEA3 family of Ets transcription factors. PEA3 is itself a target of both Wnt and HER2/neu signaling, and is highly expressed in mammary tumors induced by both Wnt1 and HER2/neu, and also in intestinal tumors where Wnt signaling is active. Thus PEA3 factors may contribute to the regulation of multiple target genes in both breast and colorectal cancers, and may be a useful anti-cancer target.

Research in the Mammary Tumorigenesis Laboratory is funded by the National Cancer Institute, the Breast Cancer Alliance, the Department of Defence Breast Cancer Research Program, and the Weinstein Foundation.

KEYWORDS: HER2/neu, Wnt, breast cancer, oncogenic signaling, target genes, PEA3, COX-2, chemoprevention

RELEVANT PUBLICATIONS

Howe, L.R., Subbaramaiah, K., Chung, W.J., Dannenberg, A.J. & Brown, A.M.C. (1999) Transcriptional activation of cyclooxygenase-2 in Wnt-1-transformed mouse mammary epithelial cells. Cancer Research 59, 1572-1577.
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Howe, L.R., Crawford, H.C., Subbaramaiah, K., Hassell, J.A., Dannenberg, A.J. & Brown, A.M.C. (2001) PEA3 is upregulated in response to Wnt1 and activates the expression of cyclooxygenase-2. J. Biol. Chem. 276, 20108-20115.
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Howe, L.R., Subbaramaiah, K., Brown, A.M.C. & Dannenberg, A.J. (2001) Cyclooxygenase-2: a target for the prevention and treatment of breast cancer. Endocrine-Related Cancer. 8, 97-114.
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Dannenberg, A.J., Altorki, N.K., Boyle, J.O., Dang, C., Howe, L.R., Weksler, B.B. & Subbaramaiah, K. (2001) Cyclo–oxygenase-2: A Pharmacologic Target for the Prevention of Cancer. Lancet Oncology. 2, 544-551.
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Mackrell, P.J., Daly, J.M., Mestre, J.R., Stapleton, P.P., Howe, L.R., Subbaramaiah, K. & Dannenberg, A.J. (2001) Elevated expression of cyclooxygenase-2 contributes to immune dysfunction in a murine model of trauma. Surgery. 130, 826-833.
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Howe, L.R. & Dannenberg, A.J. (2002) A Role for Cyclooxygenase-2 Inhibitors in the Prevention and Treatment of Cancer. Semin. Oncol. 3, Suppl. 11, 111-119.
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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. & Dannenberg, A.J. (2002) Celecoxib, a selective cyclooxygenase-2 inhibitor, protects against human Epidermal Growth Factor Receptor 2 (HER-2)/Neu-induced breast cancer. Cancer Research, 62, 5405-5407.
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Dannenberg, A.J. & Howe, L.R. (2003) The Role of COX-2 in Breast and Cervical Cancer. In: Dannenberg, A.J. & DuBois, R.N., editors. Progress in Experimental Tumor Research, Vol. 37, COX-2, A new Target for Cancer Prevention and Treatment. pp 248-264.

Howe, L.R., Watanabe, O., Leonard, J. & Brown, A.M.C. (2003) Twist is upregulated in response to Wnt1 and inhibits mouse mammary cell differentiation. Cancer Research, 63, 1906-1913.
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 Howe, L.R. & Dannenberg, A.J. (2003) COX-2 Inhibitors for the Prevention of Breast Cancer. J. Mamm. Gland Biol. & Neoplasia, 8, 31-43.
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Howe, L.R. & Brown, A.M.C. (2004) Wnt Signaling and Breast Cancer. Cancer Biol. Ther., 3, 36-41.
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Khan, K.M.F., Howe, L.R. & Falcone, D.J. (2004) Extracellular Matrix Induced Cyclooxygenase-2 Regulates Macrophage Proteinase Expression. J. Biol. Chem., 279, 22039-22046.
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Brennan, K., Gonzalez-Sancho, J.M., Castelo-Soccio, L.A., Howe, L.R. & Brown, A.M.C. (2004) Truncated mutants of the putative Wnt receptor LRP6/Arrow can stabilize ß-catenin independently of Frizzled proteins. Oncogene, 23, 4873-4884.
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Howe, L.R. (2005) Cyclooxygenase-2 and Breast Cancer. In: Yao, A.P., editor. Trends in Breast Cancer Research, In Press.

Peterlongo, P., Howe, L.R., Radice, P., Sala, P., Hong, Y.-J., Hong, S.-I., Mitra, N., Offitt, K. & Ellis, N.A. (2005) Germline mutations of AXIN2 are not associated with nonsyndromic colorectal cancer. Human Mutation, 25, 498-500.

Howe, L.R. , Chang, S-H, Tolle, K.C., Dillon, R., Young, L.J.T., Cardiff, R.D., Newman, R.A., Yang, P., Thaler, H.T., Muller, W.J., Hudis, C., Brown, A.M.C., Hla, T., Subbaramaiah, K. & Dannenberg, A.J. (2005) HER2/neu-Induced Mammary Tumorigenesis and Angiogenesis Are Reduced in Cyclooxygenase-2 Knockout Mice. Cancer Research, 65, 10113-10119.
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