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
Theoverall research interest of the Shaw lab is breast cancer progression andmetastasis. We utilize both in vitro and in vivo approaches to investigate the mechanisms by which breast carcinoma cellsacquire the ability to metastasize to secondary organs and howthey survive and grow in these foreign microenvironments. We are interested in identifying molecules or signaling pathwaysthat play an essential role in the acquisition of a metastatic phenotype and tounderstand their mechanism of action. Froma translational perspective, the goal of our work is to develop novel targetsto predict or to treat metastatic breast cancer.
Insulin Receptor Substrate Proteins
A majorfocus of the research in the lab for the past several years has been theInsulin Receptor Substrate (IRS) proteins, which are major downstream signalingintermediates of the insulin and insulin-like growth factor-1 (IGF-1)receptors. We have established that IRS-1 andIRS-2 play divergent roles in murine mammary tumor progression and are notfunctionally redundant. Specifically, wedemonstrated 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-2expression and activation. These studieswere performed using both transgenic and orthotopic models of mammary tumorprogression. Although functionaldifferences between IRS-1 and IRS-2 have been identified, the mechanism(s) bywhich these highly homologous proteins regulate distinct cellular outcomes incancer in response to common stimuli remains unknown and is the focus of ourongoing studies. Specifically, we areinterested in understanding how IRS-2 contributes to the adaptation of tumorcells to their metabolic microenvironment to promote tumor progression, therole of feedback regulation in controlling the balance of IRS expression and activityand the importance ofintracellular IRS localization for tumor cell function. With regard to the latter topic, wemade the novel observation that IRS-1 and IRS-2 have unique intracellularlocalization patterns in human breast tumors. Specifically, IRS-1 is expressed predominantly in the nucleus and IRS-2is localized either in the cytoplasm or at the cell membrane. Analysis of our dataset for associations ofIRS-2 staining patterns with core clinical parameters and clinical outcomesrevealed a significant trend toward decreased overall survival (OS) with IRS-2membrane staining. We are interested in determining the functional significanceof IRS-2 localization at the membrane and how this localization is regulated. We hypothesize that the trafficking of IRS-1 andIRS-2 to distinct intracellular compartments determines their access todownstream effectors and substrates, and as a consequence, divergent cellularresponses are elicited. From a translational perspective, signalingpathways 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 inbreast cancer. Beclin 1 is the mammalianhomolog of the yeast Atg6 gene, which plays an essential role in vesiclenucleation during the initiation of autophagy. Beclin 1 is of interest for breast cancerbecause 70% of human breast tumors exhibit decreased expression of Beclin 1when compared with normal mammary epithelial tissue. This decreased expression arises both fromthe monoallelic loss of the Beclin 1 gene in ~50% of breast tumors and aberrantDNA methylation that suppresses gene expression. Moststudies that have investigated Beclin 1 function in cancer have focused on itsrole in regulating autophagy, a normal cellular process by which cells targetcytoplasmic components, including proteins, lipids and organelles, to the lysosome for degradation. Alternative functions of Beclin 1 that couldcontribute to its role in cancer have received relatively little attention. This is significant because Beclin 1 is anessential component of the core complex that regulates endocytic trafficking,which controls the spatial and temporal dynamics of growth factor receptorsignaling. In this regard, our studies have revealed that loss of Beclin 1 enhances and sustains IGF-1R activation and downstreamsignaling to AKT in breast carcinoma cells and that these changes in signalingare associated with increased growth and invasion. We are currently studying how Beclin 1 regulates trafficking ofthe IGF-1R and how this regulation influences downstream signaling through theIRS 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.
? ? ?A postdoctoralposition is available in the Shaw lab. Candidatesmust have a PhD or MD/PhD degree in the biological sciences and be well versedin basic cell and molecular biology. Experience with mouse cancer models,preferably mammary tumor models, is a prerequisite. Interested individualsshould send their CV, a summary of research experience and the names of threereferences to Leslie.Shaw@umassmed.edu. The University of Massachusetts MedicalSchool is an affirmative action, equal opportunity employer.
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