Amplification or overexpression of HER-2/neu occurs in 20-30 percent of human breast cancers, and increased expression has been associated with poor prognosis in the patients. New medications are urgently needed to treat this disease. Several lines of evidence suggest that COX-2 is important in carcinogenesis. COX-2 deficiency protects against intestinal and skin tumor formation in experimental animals. The applicant has discovered that levels of COX-2 are elevated in HER-2/neu-positive human breast cancer. This raises the possibility that selective COX-2 inhibitors will prevent neu-induced mammary tumorigenesis, as was recently shown for colon and skin cancer.
One aim of this proposal, therefore, is to determine whether pharmacological inhibition or genetic ablation of COX-2 suppresses the formation of or inhibits the metastasis of mammary tumors in MMTV/neu transgenic mice. There is also growing preclinical evidence that ligands of the nuclear receptor PPAR gamma may be effective in preventing or treating breast cancer. The applicant has shown that PPAR gamma ligands inhibit the growth of HER-2/neu-transformed mammary epithelial cells and suppressed HER-2/neu-mediated activation of COX-2 gene expression.
A second aim will be to determine whether troglitazone, a PPRP gamma ligand, prevents mammary tumorigenesis in MMTV/neu transgenic mice or enhances the antitumor activity of Herceptin. Finally, the applicant will elucidate the mechanisms by which PPAR gamma ligands cause G1 cell cycle arrest and inhibit HER-2/neu-mediated induction of COX- 2. The results of these studies will provide the basis for making a rational decision about whether selective COX-2 inhibitors or PPAR gamma ligands should be evaluated in women with HER-2/neu-overexpressing breast cancer.
|Howe, Louise R (2007) Inflammation and breast cancer. Cyclooxygenase/prostaglandin signaling and breast cancer. Breast Cancer Res 9:210|
|Subbaramaiah, Kotha; Howe, Louise R; Port, Elisa R et al. (2006) HER-2/neu status is a determinant of mammary aromatase activity in vivo: evidence for a cyclooxygenase-2-dependent mechanism. Cancer Res 66:5504-11|
|Pavlovic, Svetlana; Du, Baoheng; Sakamoto, Kazuko et al. (2006) Targeting prostaglandin E2 receptors as an alternative strategy to block cyclooxygenase-2-dependent extracellular matrix-induced matrix metalloproteinase-9 expression by macrophages. J Biol Chem 281:3321-8|
|Kong, Gu; Kim, Hee-Tae; Wu, Kendall et al. (2005) The retinoid X receptor-selective retinoid, LGD1069, down-regulates cyclooxygenase-2 expression in human breast cells through transcription factor crosstalk: implications for molecular-based chemoprevention. Cancer Res 65:3462-9|
|Khan, K M Faisal; Howe, Louise R; Falcone, Domenick J (2004) Extracellular matrix-induced cyclooxygenase-2 regulates macrophage proteinase expression. J Biol Chem 279:22039-46|
|Terry, Mary Beth; Gammon, Marilie D; Zhang, Fang Fang et al. (2004) Association of frequency and duration of aspirin use and hormone receptor status with breast cancer risk. JAMA 291:2433-40|
|Subbaramaiah, Kotha; Dannenberg, Andrew J (2003) Cyclooxygenase 2: a molecular target for cancer prevention and treatment. Trends Pharmacol Sci 24:96-102|
|Howe, Louise R; Dannenberg, Andrew J (2003) COX-2 inhibitors for the prevention of breast cancer. J Mammary Gland Biol Neoplasia 8:31-43|
|Dannenberg, Andrew J; Subbaramaiah, Kotha (2003) Targeting cyclooxygenase-2 in human neoplasia: rationale and promise. Cancer Cell 4:431-6|
|Dannenberg, Andrew J; Howe, Louise R (2003) The role of COX-2 in breast and cervical cancer. Prog Exp Tumor Res 37:90-106|
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