The progression of DCIS to invasive carcinoma is a poorly understood key step in breast tumor progression. We have previously demonstrated that molecular changes occur in all cell types during tumor progression and that the loss of myoepithelial cells leads to invasive tumors in MCF10DCIS xenografts. We have characterized the comprehensive gene expression profiles of putative progenitor-like and differentiated myoepithelial cells from normal human breast tissue and identified markers that can be used for their identification. Based on our data we hypothesize that the differentiation of progenitors to myoepithelial cells is progressively inhibited by signals coming from tumor epithelial cells and cells composing the microenvironment. As a consequence of this, the myoepithelial cell layer is gradually lost and eventually disappears, leading to transition to Invasion. We propose three specific aims to test these hypotheses.
Aim 1 : To identify molecular determinants of normal myoepithelial cell differentiation and their abnormalities in DCIS. We will isolate CD10+ subpopulations of cells from normal breast tissue of healthy women and BRCA1 mutation carriers, and from different subtypes of DCIS. Molecular profiles of each of the cell populations will be characterized using genome-wide approaches followed by validation in a larger set of samples at the single cell level.
Aim 2 : To determine if abnormalities of myoepithelial differentiation in DCIS correlate with the risk of progression to invasive disease. We will determine if the expression of regulators of myoepithelial cell differentiation in DCIS is associated with invasive progression.
Aim 3 : To test if modulating signaling pathways involved.in myoepithelial cell differentiation would effect progression to invasion. Using primary cell culture models, we will determine if perturbations of regulators of myoepithelial cell differentiation lead to loss of myoepithelial cells and progression to invasion. Identification of determinants of normal myoepithelial cell differentiation and their abnormalities in DCIS would improve our understanding of stem cell differentiation and provide novel prognostic markers and targets for therapeutic and preventative interventions.
(See Instructions): The transition of DCIS to invasive carcinoma is a poorly understood key event in breast tumor progression The proposed project will investigate normal myoepithelial cell differentiation programs and whether their perturbation in DCIS may explain progression to invasion using primary human tissue samples Understanding these processes may open new venues for cancer therapy and prevention.
|Hines, William C; Yaswen, Paul; Bissell, Mina J (2015) Modelling breast cancer requires identification and correction of a critical cell lineage-dependent transduction bias. Nat Commun 6:6927|
|Diamond, Marc I; Cai, Shirong; Boudreau, Aaron et al. (2015) Subcellular localization and Ser-137 phosphorylation regulate tumor-suppressive activity of profilin-1. J Biol Chem 290:9075-86|
|Weigelt, Britta; Ghajar, Cyrus M; Bissell, Mina J (2014) The need for complex 3D culture models to unravel novel pathways and identify accurate biomarkers in breast cancer. Adv Drug Deliv Rev 69-70:42-51|
|Hines, William C; Su, Ying; Kuhn, Irene et al. (2014) Sorting out the FACS: a devil in the details. Cell Rep 6:779-81|
|Veiseh, Mandana; Kwon, Daniel H; Borowsky, Alexander D et al. (2014) Cellular heterogeneity profiling by hyaluronan probes reveals an invasive but slow-growing breast tumor subset. Proc Natl Acad Sci U S A 111:E1731-9|
|Vidi, Pierre-Alexandre; Bissell, Mina J; Lelièvre, Sophie A (2013) Three-dimensional culture of human breast epithelial cells: the how and the why. Methods Mol Biol 945:193-219|
|Mori, Hidetoshi; Lo, Alvin T; Inman, Jamie L et al. (2013) Transmembrane/cytoplasmic, rather than catalytic, domains of Mmp14 signal to MAPK activation and mammary branching morphogenesis via binding to integrin ?1. Development 140:343-52|
|Lee, Somin Eunice; Alivisatos, A Paul; Bissell, Mina J (2013) Toward plasmonics-enabled spatiotemporal activity patterns in three-dimensional culture models. Syst Biomed (Austin) 1:|
|Bascom, Jamie L; Radisky, Derek C; Koh, Eileen et al. (2013) Epimorphin is a novel regulator of the progesterone receptor isoform-a. Cancer Res 73:5719-29|
|Correia, Ana Luísa; Mori, Hidetoshi; Chen, Emily I et al. (2013) The hemopexin domain of MMP3 is responsible for mammary epithelial invasion and morphogenesis through extracellular interaction with HSP90?. Genes Dev 27:805-17|
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