title: Functional viability profiles of breast cancer.
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.
  
  
  CONCLUSIONS
  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.
authors: The Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London, United Kingdom.
authors: Rachel
authors: R
authors: Brough
authors: Jessica R
authors: JR
authors: Frankum
authors: David
authors: D
authors: Sims
authors: Alan
authors: A
authors: Mackay
authors: Ana M
authors: AM
authors: Mendes-Pereira
authors: Ilirjana
authors: I
authors: Bajrami
authors: Sara
authors: S
authors: Costa-Cabral
authors: Rumana
authors: R
authors: Rafiq
authors: Amar S
authors: AS
authors: Ahmad
authors: Maria Antonietta
authors: MA
authors: Cerone
authors: Rachael
authors: R
authors: Natrajan
authors: Rachel
authors: R
authors: Sharpe
authors: Kai-Keen
authors: KK
authors: Shiu
authors: Daniel
authors: D
authors: Wetterskog
authors: Konstantine J
authors: KJ
authors: Dedes
authors: Maryou B
authors: MB
authors: Lambros
authors: Teeara
authors: T
authors: Rawjee
authors: Spiros
authors: S
authors: Linardopoulos
authors: Jorge S
authors: JS
authors: Reis-Filho
authors: Nicholas C
authors: NC
authors: Turner
authors: Christopher J
authors: CJ
authors: Lord
authors: Alan
authors: A
authors: Ashworth
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling / Q000639:trends; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism
chemical_list: D011960:Receptors, Estrogen; D011494:Protein Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human