Leslie M Shaw PhD
|Institution||University of Massachusetts Medical School|
|Department||Molecular, Cell and Cancer Biology|
|Address||University of Massachusetts Medical School|
364 Plantation Street, LRB
Worcester MA 01605
|Institution||UMMS - Programs, Centers and Institutes|
BREAST CANCER METASTASIS
The overall research interest of the Shaw lab is breast cancer progression and metastasis. We utilize both in vitro and in vivo approaches to investigate the mechanisms by which breast carcinoma cells acquire the ability to metastasize to secondary organs and how they survive and grow in these foreign microenvironments. We are interested in identifying molecules or signaling pathways that play an essential role in the acquisition of a metastatic phenotype and to understand their mechanism of action. From a translational perspective, the goal of our work is to develop novel targets to predict or to treat metastatic breast cancer.
Insulin Receptor Substrate Proteins
A major focus of the research in the lab for the past several years has been the Insulin Receptor Substrate (IRS) proteins, which are major downstream signaling intermediates of the insulin and insulin-like growth factor-1 (IGF-1) receptors. We have established that IRS-1 and IRS-2 play divergent roles in murine mammary tumor progression and are not functionally redundant. Specifically, we demonstrated that metastasis is significantly impaired in the absence of IRS-2, but it is enhanced in tumor cells that lack IRS-1, but have increased IRS-2 expression and activation. These studies were performed using both transgenic and orthotopic models of mammary tumor progression. Although functional differences between IRS-1 and IRS-2 have been identified, the mechanism(s) by which these highly homologous proteins regulate distinct cellular outcomes incancer in response to common stimuli remains unknown and is the focus of our ongoing studies. Specifically, we are interested in understanding how IRS-2 contributes to the adaptation of tumor cells to their metabolic microenvironment to promote tumor progression, the role of feedback regulation in controlling the balance of IRS expression and activity and the importance of intracellular IRS localization for tumor cell function. With regard to the latter topic, we made the novel observation that IRS-1 and IRS-2 have unique intracellular localization patterns in human breast tumors. Specifically, IRS-1 is expressed predominantly in the nucleus and IRS-2 is localized either in the cytoplasm or at the cell membrane. Analysis of our dataset for associations of IRS-2 staining patterns with core clinical parameters and clinical outcomes revealed a significant trend toward decreased overall survival (OS) with IRS-2 membrane staining. We are interested in determining the functional significance of IRS-2 localization at the membrane and how this localization is regulated. We hypothesize that the trafficking of IRS-1 and IRS-2 to distinct intracellular compartments determines their access to downstream effectors and substrates, and as a consequence, divergent cellular responses are elicited. From a translational perspective, signaling pathways that are activated through IRS-2 or regulate IRS expression and/orlocalization could be exploited for therapeutic intervention of metastasis.
We are interested in autophagy-independent functions of Beclin 1 in breast cancer. Beclin 1 is the mammalian homolog of the yeast Atg6 gene, which plays an essential role in vesicle nucleation during the initiation of autophagy. Beclin 1 is of interest for breast cancer because 70% of human breast tumors exhibit decreased expression of Beclin 1 when compared with normal mammary epithelial tissue. This decreased expression arises both from the monoallelic loss of the Beclin 1 gene in ~50% of breast tumors and aberrant DNA methylation that suppresses gene expression. Most studies that have investigated Beclin 1 function in cancer have focused on its role in regulating autophagy, a normal cellular process by which cells target cytoplasmic components, including proteins, lipids and organelles, to the lysosome for degradation. Alternative functions of Beclin 1 that could contribute to its role in cancer have received relatively little attention. This is significant because Beclin 1 is an essential component of the core complex that regulates endocytic trafficking, which controls the spatial and temporal dynamics of growth factor receptor signaling. In this regard, our studies have revealed that loss of Beclin 1 enhances and sustains IGF-1R and EGFR activation and downstream signaling in breast carcinoma cells and that these changes in signaling are associated with increased growth and invasion. We are currently studying how Beclin 1 regulates trafficking of the IGF-1R and how this regulation influences downstream signaling through the IRS proteins to impact tumor cell function.
Rotation projects in the lab include: 1) Investigating howIRS-1 and IRS-2 regulate distinct downstream signaling pathways; 2)Investigating how stimuli in the tumor microenvironment and oncogenic signalsinfluence feedback regulation of IRS function; 3) Investigating how IRSintracellular localization is regulated and the importance for breast carcinomacell function; 4) Investigating how the IRS proteins influence IGF-1Rtrafficking; 5) Investigating the role of Beclin 1 in the regulation IGF-1R endocytictrafficking and downstream Akt activation; 6) Investigating the mechanism bywhich Beclin 1 regulates tumor cell invasion. Basic cell biology, biochemistry and molecularbiology techniques will be used. Inaddition, we have both transgenic and orthotopic mouse models of breast cancerestablished in the lab for studying metastasis.
Rotation projects in the lab include: 1) Investigating how IRS-1 and IRS-2 regulate distinct downstream signaling pathways; 2) Investigating how stimuli in the tumor microenvironment and oncogenic signals influence feedback regulation of IRS function; 3) Investigating how IRS intracellular localization is regulated and the importance for breast carcinoma cell function; 4) Investigating how the IRS proteins influence IGF-1R trafficking; 5) Investigating the role of Beclin 1 in the regulation IGF-1R endocytic trafficking and downstream Akt activation; 6) Investigating the mechanism by which Beclin 1 regulates tumor cell invasion. Basic cell biology, biochemistry and molecular biology techniques will be used. In addition, we have both transgenic and orthotopic mouse models of breast cancer established in the lab for studying metastasis.
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