We use complex three-dimensional tissue culture models of the tumor microenvironment to address important outstanding questions in the molecular oncology of breast cancer.
1. Regulation of EGFR ligand bioavailabity.
Activation of members of the Epidermal Growth Factor Receptor family is a key feature of many solid tumors, including breast cancer. Activation of these receptors requires binding by ligands such as EGF, Amphiregulin or TGFa which are synthesized as transmembrane precursors. We are studying the mechanisms by which the production of these growth factors is regulated at both the transcriptional and post-transcriptional stages. We have shown that a metal-dependent protease, TACE/ADAM17, is a critical regulator of EGFR ligand bioavailability as it cleaves both Amphiregulin and TGFa at the cell surface. This implicates TACE as a drugable therapeutic target upstream of EGFR.
2. Investigation of the macrophage-tumor cell dialogue in the breast tumor microenvironment.
Cells of the immune system have long been observed in tumors in close association with neoplastic cells. High levels of macrophage infiltration frequently correlated with increased angiogenesis, tumor invasion and poor prognosis. We are developing three-dimension ex vivo models of the breast tumor microenvironment to explore in detail the interactions between macrophages and breast cancer cells. Understanding the dialogue between these cell types should yield potential new therapeutic targets in the tumor microenvironment.
Faddy HM, Smart CE, Xu R, Lee GY, Kenny PA, Feng M, Rao R, Brown MA, Bissell MJ, Roberts-Thomson SJ and Monteith GR. Localization of plasma membrane and secretory calcium pumps in the mammary gland. Biochem Biophys Res Commun. 369(3):977-81 (2008)
Kenny PA and Bissell MJ Targeting TACE-dependent EGFR ligand shedding in breast cancer. J Clin Invest 117 (2) 337-345 (2007)
Kenny PA 3D extracellular matrix culture models of EGFR signaling and drug response. Biochemical Society Transactions 35(4):665-668 (2007)
Kenny PA TACE: a new target in EGFR-dependent tumors. Differentiation 75(9) 800-808 (2007)
McBryan J, Howlin J, Kenny PA, Shioda T and Martin F ERα-CITED1 co-regulated genes expressed during pubertal mammary gland development: implications for breast cancer prognosis. Oncogene 26(44):6406-6419 (2007)
Kenny PA, Lee GY, Myers CA, Neve RM, Semeiks JR, Spellman PT, Lorenz K, Lee EH, Barcellos-Hoff MH, Petersen OW, Gray JW, Bissell MJ The morphologies of breast cancer cell lines in three-dimensional assays correlate with their profiles of gene expression. Molecular Oncology 1(1) 84-96 (2007)
Lee GY, Kenny PA, Lee EH and Bissell MJ 3D culture models of normal and malignant breast epithelial cells. Nature Methods 4(4):359-365 (2007)
Kenny PA, Lee GY, and Bissell MJ (2007) Targeting the tumor microenvironment. Frontiers in Bioscience 12:3468-3474