Brough, R., Frankum, J. R., Sims, D., Mackay, A., Mendes-Pereira, A. M., Bajrami, I., Costa-Cabral, S., Rafiq, R., Ahmad, A. S., Cerone, M. A., Natrajan, R., Sharpe, R., Shiu, K. K., Wetterskog, D., Dedes, K. J., Lambros, M. B., Rawjee, T., Linardopoulos, S., Reis, J. S., Turner, N. C., Lord, C. J., Ashworth, A. (2011) Functional Viability Profiles of Breast Cancer. CANCER DISCOVERY, 1 (3). pp. 260-273. ISSN 2159-8274

Full text not available from this repository.

Abstract

The design of targeted therapeutic strategies for cancer has largely been driven by the identification of tumor-specific genetic changes. However, the large number of genetic alterations present in tumor cells means that it is difficult to discriminate between genes that are critical for maintaining the disease state and those that are merely coincidental. Even when critical genes can be identified, directly targeting these is often challenging, meaning that alternative strategies such as exploiting synthetic lethality may be beneficial. To address these issues, we have carried out a functional genetic screen in >30 commonly used models of breast cancer to identify genes critical to the growth of specific breast cancer subtypes. In particular, we describe potential new therapeutic targets for PTEN-mutated cancers and for estrogen receptor-positive breast cancers. We also show that large-scale functional profiling allows the classification of breast cancers into subgroups distinct from established subtypes. SIGNIFICANCE: Despite the wealth of molecular profiling data that describe breast tumors and breast tumor cell models, our understanding of the fundamental genetic dependencies in this disease is relatively poor. Using high-throughput RNA interference screening of a series of pharmacologically tractable genes, we have generated comprehensive functional viability profiles for a wide panel of commonly used breast tumor cell models. Analysis of these profiles identifies a series of novel genetic dependencies, including that of PTEN-null breast tumor cells upon mitotic checkpoint kinases, and provides a framework upon which additional dependencies and candidate therapeutic targets may be identified. Cancer Discovery; 1(3);260-73. (C) 2011 AACR.

Item Type:	Article
Authors (ICR Faculty only):	Ashworth, Alan and Lord, Chris and Linardopoulos, Spiros and Reis-Filho, Jorge
All Authors:	Brough, R., Frankum, J. R., Sims, D., Mackay, A., Mendes-Pereira, A. M., Bajrami, I., Costa-Cabral, S., Rafiq, R., Ahmad, A. S., Cerone, M. A., Natrajan, R., Sharpe, R., Shiu, K. K., Wetterskog, D., Dedes, K. J., Lambros, M. B., Rawjee, T., Linardopoulos, S., Reis, J. S., Turner, N. C., Lord, C. J., Ashworth, A.
Additional Information:	ISI Document Delivery No.: 832DY Times Cited: 1 Cited Reference Count: 44 Brough, Rachel Frankum, Jessica R. Sims, David Mackay, Alan Mendes-Pereira, Ana M. Bajrami, Ilirjana Costa-Cabral, Sara Rafiq, Rumana Ahmad, Amar S. Cerone, Maria Antonietta Natrajan, Rachael Sharpe, Rachel Shiu, Kai-Keen Wetterskog, Daniel Dedes, Konstantine J. Lambros, Maryou B. Rawjee, Teeara Linardopoulos, Spiros Reis-Filho, Jorge S. Turner, Nicholas C. Lord, Christopher J. Ashworth, Alan Breakthrough Breast Cancer; Cancer Research UK; Stand Up To Cancer-American Association for Cancer Research Dream Team[SU2C-AACR-DT0409]; National Health Service This work was supported by grants from Breakthrough Breast Cancer and Cancer Research UK. Research supported by Stand Up To Cancer-American Association for Cancer Research Dream Team Translational Cancer Research Grant, Grant Number SU2C-AACR-DT0409. We also acknowledge National Health Service funding to the National Institute for Health Research Royal Marsden Hospital Biomedical Research Centre. Amer assoc cancer research Philadelphia
Uncontrolled Keywords:	gene-expression mutant-cells pten kinase mutations therapy identification instability deficiency carcinomas
Research teams:	ICR divisions > Breast Cancer Research > Drug Target Discovery ICR divisions > Cancer Therapeutics > Drug Target Discovery Closed research groups > Molecular Pathology ICR divisions > Breast Cancer Research > Target Discovery & Apoptosis ICR divisions > Cancer Therapeutics > Target Discovery & Apoptosis ICR divisions > Breast Cancer Research > Gene Function ICR divisions > Molecular Pathology > Gene Function
Depositing User:	Barry Jenkins
Date Deposited:	31 Oct 2011 13:25
Last Modified:	12 Feb 2014 16:12
URI:	http://publications.icr.ac.uk/id/eprint/11109

Actions (login required)

View Item