About the Project
Women who have undergone surgery for breast cancers often have additional chemotherapy to kill residual cancer cells and prevent recurrence. Unfortunately, 30-40% of these patients’ tumour cells are resistant to these treatments. Previously, we identified mutations in MCPH1, a DNA damage response gene, as a cause of primary microcephaly (OMIM 251200) and premature chromosome condensation (PCC)1,2. A number of lines of evidence indicate that MCPH1 is a tumour supressor gene3.
We have reported that the levels of MCPH1, which is involved in the regulation of BRCA1 and BRCA2, were reduced in 29% of breast cancers 4. These reductions were associated with increasing tumour grade and poor survival. We also demonstrated that MCPH1 regulates resistance to the chemotherapeutic agents Paclitaxel and Parp inhibitors in a mechanism yet to be defined.
This project will investigate the link between MCPH1 expression and response to chemotherapy in breast cancer. We will also determine the effect of MCPH1 expression on the response of cultured cells to chemotherapeutics, using cancer cell lines. In this study we propose to identify the molecular mechanisms involved in this resistance by performing pathway analysis on three different data sets. Previously MCPH1 gene expression array (Affymetrix Exon 1.0) and Mass Spectrometry protein interaction studies have been performed. Furthermore, a large scale druggable whole genome siRNA screen has recently been completed 6. Suitable pathways will be investigated in detail.
Biomarkers much as MCPH1 will potentially enable us to identify new approaches to treat breast cancer patients that are resistant to current treatments.
This project will provide research training in a range of techniques including siRNA gene knockdown, cell culture, RNA extraction, Affymetrix and pathway analysis, Real time PCR, immunofluorescence, western blotting, live cell imaging and drug cytoxicity assays.
References
1. Jackson AP, Eastwood H, Bell SM, Adu J, Toomes C, Carr I, Roberts E, Hampshire D, Crow YJ, Mighell AJ, Karbani G, Rashid Y, Muller RF, Markham AF, Woods CG (2002) Identification of Microcephalin, a protein implicated in determining the size of the human brain. Am J Hum Genet 71:136-142.
2. Trimborn M, Bell SM, Felix C, Rashid Y, Jafri H, Griffiths PD, Neumann LM, Krebs A, Reis A, Sperling K, Neitzel H, Jackson AP (2004) Microcephalin is a regulator of chromosome condensation. Am J Hum Genet 75: (2):261-266.
3. Lin S-Y, Liang Y, Li K (2010) Multiple roles of BRIT1/MCPH1 in DNA damage response, DNA repair and cancer suppression. Yonsei Med J 51(3):295-301.
4. Richardson J, Shaaban AM, Kamal M, Alisary R, Ellis I, Speirs V, Green A, Bell SM (2011) Microcephalin is a novel prognostic marker in breast cancer associated with BRCA1 inactivation. Breast Cancer Res Treat, 127(3):639-48.
5. Brüning-Richardson A, Bond J, Richardson J, Alsiary R, Cairns DA, McCormack L, Hutson R, Burns P, Wilkinson N, Hall G, Morrison EE, Bell SM (2011) ASPM and microcephalin expression in ovarian ascites correlates with tumour grade and survival. Br J Cancer 104(10):1602-10.
6. Adams M, Cookson VJ, Higgins J, Martin HL, Tomlinson DC, Bond J, Morrison EE and Bell SM (2013) A high-throughput assay to identify modifiers of premature chromosome condensation. J Biomolecular Screening (e-pub Sept 2013).
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