Identification of microRNAs that regulate cell-fate decisions & differentiation in the mammary gland
Project type
PhD
| Supervisor(s) | Division | |
| (Primary) | Stem Cells and Cancer | .(JavaScript must be enabled to view this email address) |
| (Co-supervisor) | Stem Cells and Cancer | .(JavaScript must be enabled to view this email address) |
Dr Bhupinder Pal (Co-supervisor) |
Stem Cells and Cancer | .(JavaScript must be enabled to view this email address) |
Details of project
The expression of genes in eukaryotic cells is tightly regulated by several mechanisms including microRNA (miRNA)-mediated mRNA degradation. Several miRNAs have been found to regulate normal development and oncogenesis. However, there is little information on miRNAs that are important for the generation of mammary epithelial lineages and whose deregulation leads to breast cancer.
Over the last few years we have dissected four distinct epithelial subtypes in the mammary gland. These include mammary stem cells, two luminal progenitor subsets and mature luminal cells. Gene and miRNA expression signatures have now been obtained for these subsets. Our next goal is to understand the mechanisms that regulate self-renewal, cell-fate decisions and differentiation within the mammary gland.
The project outlined here aims to determine the role of microRNAs in establishing the epithelial hierarchy. This will involve expressing miRNAs or anti-miRNAs in primary epithelial subsets, and using in vitro cell-based assays to ascertain their effects on proliferation and differentiation. Finally, specific miRNAs will be introduced into mammary stem cells or the germ-line via ES cell technology for the analysis of effects on mammary gland development and tumourigenesis.
Project references
- Bracken CP, Gregory PA, Kolesnikoff N, Bert AG, Wang J, Shannon MF, Goodall GJ. A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res. 2008 68(19):7846-54.
- Davalos V and Esteller M. MicroRNAs and cancer epigenetics: a macrorevolution. Curr Opin Oncol. 2010 22(1):35-45.
- Tavazoie SF, Alarcón C, Oskarsson T, Padua D, Wang Q, Bos PD, Gerald WL, Massagué J. (2008) Endogenous human microRNAs that suppress breast cancer metastasis. Nature. 2008 451(7175):147-52.
Research interests
Our laboratory is interested in identifying transcriptional regulators that govern mammary gland development and whose perturbation leads to breast cancer. By studying normal and malignant breast epithelial cells, our long-term goal is to identify markers and potential therapeutic targets against breast cancer.
Selected publications
- Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat M-L,Wu L, Lindeman GJ, Visvader JE. Generation of a functional mammary gland from a single stem cell. Nature. 2006 439;84-88.
- Bouras T, Pal B, Vaillant F, Harburg G, Asselin-Labat M-L, Oakes SR, Lindeman GJ, Visvader JE. Notch signaling regulates mammary stem cell function and luminal cell fate commitment. Cell Stem Cell. 2008 3(4);429-4.
- Lim E, Wu D, Pal B, Bouras T, Asselin-Labat M-L, Vaillant F, Yagita H, Lindeman GJ, Smyth GK, Visvader JE. (2010) Transcriptome analyses of mouse and human mammary cell subpopulations reveals multiple conserved genes and pathways. Breast Cancer Research. 2010 12(2);R21.
- Lim E, Vaillant F, Wu D, Forrest NC, Pal B, Hart AH, Asselin-Labat M-L, Gyorki DE, Ward T, Partanen A, Feleppa F, Huschtscha LI, Thorne HJ, kConFab, Fox SB, Yan M, French JD, Brown MA, Smyth GK, Visvader JE, Lindeman GJ. Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nature Medicine. 2009 15(8);907-13.
Research theme
Cancer
Scientific discipline
- Cell Biology
- Molecular Biology
- Stem Cell Biology
Keywords
Breast Cancer