Margot Ip

Research Overview:

The focus of this laboratory is on the identification and characterization of specific pathways regulating the growth of normal and malignant mammary epithelium, with the overall objective of elucidating pathways which may be altered during the development of breast cancer, and/or which may be targeted for therapy or chemoprevention.

A. Proliferative role of tumor necrosis factor (TNF) in normal and malignant breast epithelium

Tumor necrosis factor-alpha (TNF) is a pleiotropic cytokine which we have shown to be a multifunctional regulator of normal postnatal mammary gland development. Current efforts in the laboratory are devoted to a determination of whether tumor necrosis factor (TNF), which stimulates the growth and morphological development of normal mammary epithelial cells, as well as mammary tumor cells in primary culture, may act in an autocrine or paracrine manner to stimulate the growth of breast tumors, and if so to design therapeutic strategies to counteract this activity. A major part of these studies involves a determination of the signal transduction pathways by which TNF exerts its effects in primary cultures of normal and malignant breast epithelial cells, so that potential therapeutic targets can be identified. Additionally, TNF null mice, as well as mice lacking specific TNF downstream effectors, are being used as tools to determine the biological and molecular events that are altered and mediated, respectively, by TNF in the mammary gland. TNF null mice are also being used to determine whether TNF plays a stimulatory role in mammary tumorigenesis in mice which overexpress her2/erbB2 in the mammary epithelium.

B. Chemoprevention of breast cancer with conjugated linoleic acid

Our previous studies demonstrated that conjugated linoleic acid (CLA), a family of C18 fatty acids with conjugated double bonds, inhibits rat mammary carcinogenesis and angiogenesis. The naturally occurring c9,t11-CLA isomer, as well as the t10,c12-CLA isomer which is a component of synthetic CLA mixtures, were equally effective. Unexpectedly, in recent studies using a clinically relevant breast cancer model, namely transgenic mice overexpressing her2/erbB2 in the mammary epithelium, we found that t10,c12-CLA accelerated mammary tumorigenesis and stimulated lung metastasis. Dietary supplementation with this isomer was also shown to dramatically alter the mouse mammary stroma. Current studies in the laboratory are focused on a determination of the biological and molecular mechanisms by which each of the CLA isomers exert its effects, with the goal of understanding the opposite effects of the isomers in different mammary tumor models.