Paraic Kenny, Director



We use complex three-dimensional tissue culture models of the tumor microenvironment to address important outstanding questions in the molecular oncology of breast cancer.

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1. Regulation of EGFR ligand bioavailability.

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 are particularly interested in the role of Amphiregulin as an effector of the estrogen receptor in breast cancer in both the treatment-naïve and endocrine-resistant settings. We are running a prospective clinical trial to examine the utility of serum Amphiregulin as a biomarker for the presence of breast cancer and for response to therapy.

2. Novel drug targets in triple-negative breast cancer.
Triple-negative breast cancer lacks expression of ER, PR and HER2 which are the drug targets for our most commonly used breast cancer targeted therapies. This is frequently an aggressive disease which disproportionately affects young women. Our goal is to better understand the biology that underlies triple-negative breast cancer so that we may identify and validate appropriate targets for therapy.

3. MicroRNAs in lobular breast carcinoma.
Lobular breast carcinomas comprise approximately 1/6 of all breast cancers and are being diagnosed at an increasing rate. The biology of the disease is poorly understood and there are no effective biomarkers for distinguishing high from low-risk lesions. In collaboration with Olivier Loudig, we have generated microRNA profiles from a large number of clinical specimens and identified a group of microRNAs associated with progression to advanced lesions. We found that expression of one of these microRNAs, hsa-mir-375, in non-malignant mammary epithelial cells dramatically disrupted their ability to form quiescent polarized mammary acini in 3D culture. We are now focused on identifying the key targets of this microRNA and defining the mechanisms by which they contribute to lobular neoplasia.

4. 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.