Research

The research interests of the Shaw Lab are aimed at understanding the mechanisms involved in the progression of cancer from carcinoma in situ to metastatic disease.  Progression requires that these cells acquire the abilities to invade, survive in non-breast tissues and stimulate angiogenesis. Breast cancer is the primary model system that we are studying and our focus is to identify molecules or signaling pathways that play an essential role in the acquisition of a metastatic phenotype and to understand their mechanism of action.

Insulin Receptor Substrate Signaling in Breast Cancer      

One of the major interests of the lab is the contribution of Insulin Receptor Substrate (IRS)-dependent signaling pathways to breast cancer progression.  The IRS proteins are adaptor proteins that are recruited to surface receptors in response to ligand binding where they organize complexes that initiate intracellular signaling cascades.  The IRS proteins are the major downstream substrates of the insulin and IGF-1 receptors, the latter of which is over-expressed in breast cancer and is associated with a poor patient prognosis. We have taken an in vivo approach to investigate the function of IRS-1 and IRS-2 in mammary tumor development and progression to metastasis using IRS knockout mice and a transgenic model of mammary tumor progression.  Our results have revealed that IRS-1 and IRS-2 play distinct roles in mammary tumor metastasis.  Specifically, mammary tumors that lack IRS-2 are significantly diminished in their ability to metastasize and IRS-1 cannot substitute for this function.  In fact, tumors lacking IRS-1, and expressing only IRS-2, are more metastatic than their normal counterparts.  Ongoing studies in the lab are aimed at investigating the differences between IRS-1 and IRS-2 signaling and their regulation of expression and function.   Projects include elucidating the mechanism(s) by which IRS-2 expression is regulated and how it promotes metastasis.  We are also investigating the negative feedback regulation of IRS-1 expression and function and the role this regulation plays in promoting breast cancer metastasis.  We continue to take both in vitro and in vivo approaches to investigate IRS function in breast cancer.

The α6β4 Integrin and Carcinoma Cell Invasion and Metastasis

A second research interest of the lab is the α6β4 integrin, a cell surface adhesion receptor for the laminin family of extracellular matrix proteins. The α6β4 integrin was initially identified as a tumor-related antigen expressed in metastatic cancer, and since then, many studies have reported a strong association of α6β4 expression with carcinoma progression.  Importantly, expression of the β4 subunit correlates with a poor prognosis in patients with many types of cancer, including breast cancer.  Functional studies have demonstrated that the α6β4 integrin contributes to tumor progression through its ability to promote carcinoma cell invasion and survival. The α6β4 receptor is distinct from other integrin receptors because the β4 subunit contains a 1000 amino acid cytoplasmic domain. This cytoplasmic domain is essential for the α6β4 integrin’s mechanical involvement in mediating adhesive interactions, as well as for its ability to activate intracellular signaling pathways. Our interest in the IRS proteins initially arose from our discovery that the IRS proteins are intermediates in the α6β4-dependent activation of Phosphoinositide 3-OH kinase (PI3K) and promotion of carcinoma invasion. More recently, we identified a tyrosine residue in the β4 cytoplasmic domain that is required for the ability of the α6β4 integrin to promote breast carcinoma cell invasion and survival.  We have demonstrated that Y1494 is a binding site for the tyrosine phosphatase SHP-2, which is a positive regulator of many signaling pathways, including the Src family kinases (SFKs). Ongoing projects in the lab are continuing these mechanistic studies of the α6β4 integrin.