2012; doi: 10.1101/cshperspect.a013516Cold Spring Harb Perspect Biol  Kornelia Polyak On Using Functional Genetics to Understand Breast Cancer Biology

Subject Collection The Mammary Gland as an Experimental Model

Gland Development and CancerOn the Role of the Microenvironment in Mammary

Derek RadiskyMetalloproteinases Couple Form with FunctionOn How Mammary Gland Reprogramming

Bonnie F. Sloane

Breast Cancer BiologyOn Using Functional Genetics to Understand

Kornelia PolyakMammary Gland DevelopmentOn Molecular Mechanisms Guiding Embryonic

Gertraud W. Robinson

the Mammary GlandOn Oncogenes and Tumor Suppressor Genes in

Rushika M. Perera and Nabeel Bardeesy

On Stem Cells in the Human BreastMark A. LaBarge

CancerOn Leukocytes in Mammary Development and

Cyrus M. GhajarDiscovery, Function, and Current StatusOn Murine Mammary Epithelial Stem Cells:

Jeffrey M. Rosen

Differentiation and Breast TumorigenesisOn Chromatin Remodeling in Mammary Gland

Kornelia Polyak

On In Vivo Imaging in CancerDavid Piwnica-Worms

On Hormone Action in the Mammary GlandJ.M. Rosen

Models of Breast Cancerin Context--The Utility and Limitations of Mouse Choosing a Mouse Model: Experimental Biology

Alexander D. Borowsky

Breast CancerTGF-b Biology in Mammary Development and

Harold Moses and Mary Helen Barcellos-Hoff Tumor ProgressionMechanosignaling in Normal Development and Mammary Gland ECM Remodeling, Stiffness, and

Pepper Schedin and Patricia J. Keely

Engineered MiceHouse Mouse to the Development of GeneticallyBiologist: From the Initial Observations in the A Compendium of the Mouse Mammary Tumor

Robert D. Cardiff and Nicholas Kenney

Mammary Gland DevelopmentMolecular Mechanisms Guiding Embryonic

Pamela Cowin and John Wysolmerski

http://cshperspectives.cshlp.org/cgi/collection/ For additional articles in this collection, see

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On Using Functional Genetics to UnderstandBreast Cancer Biology

Kornelia Polyak

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston,Massachusetts 02215

Correspondence: kornelia_polyak@dfci.harvard.edu

The completion of the human genome proj-ect has greatly accelerated discovery of novel

genes and their structural abnormalities impli-cated in various human diseases, including can-cer, but it has not revealed much informationabout their functions. Even if we just considercoding genes, which constitute only a small partof the genome, our understanding of their phys-iologic roles is limited to a fraction of them.Functional genomics studies, aimed at the iden-tification and characterization of all genes in thegenome based on their function, until recentlycould only be conducted in lower organisms, aslarge-scale screens were not feasible in mamma-lian cells. This all changed about a decade agowith the discovery of RNA interference (RNAi).Since then this technology has been one of themost useful and fruitful tools in cancer research.

Ashworth and Bernards (2011) provide anexcellent overview of recent functional genomicsstudies of breast cancer and other human cancersthat aimed to identify novel tumor suppressorsand oncogenes and to dissect the molecular basisof therapeutic resistance and tumor progression.Initially such screens involved small sets of genesbased on their known biochemical functions(e.g., deubiquintylating enzymes) or relativelyeasy “druggability” (e.g., kinases and G-pro-tein-coupled receptors [GPCRs]), but more re-cently genome-wide screens have been feasible

even in human cells. However, with the ever-increasing number of noncoding RNAs uncov-ered and numerous alternative transcripts foreach gene, the definition of “genome-wide” isbecoming more and more difficult, as is confir-mation that specific targeting has been achieved(especially challenging for certain groups ofnoncoding RNAs and alternative transcripts).

Ashworth and Bernards discuss several ex-amples of loss-of-function and gain-of-func-tion screens and provide a detailed descriptionof the technical aspects of these studies. Thediscussion of potential technical problems isespecially useful, because these technologiespromise to provide solid preclinical data for fu-ture clinical studies. However, translating theresults is still limited by the availability of suit-able drugs, although the potential therapeuticuse of short hairpin RNA (shRNA) and RNAi isalso being explored.

One of the most exciting applications ofRNAi screens is to identify synthetic lethal inter-actions in cancer cells as this approach wouldensure tumor specificity and minimize sideeffects. Among all synthetic lethal interactionsidentified thus far in tumors (although this wasnot discovered in a functional genomics screen),the discovery that inhibition of poly(ADP-ribose)polymerase (PARP) selectively kills BRCA1- orBRCA2-deficient cancer cells (Farmer et al.

Editors: Mina J. Bissell, Kornelia Polyak, and Jeffrey M. Rosen

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2005) has had the most clinical impact. Basedon promising preclinical studies, several clinicaltrials are under way using various PARP inhib-itors in breast cancer (BRCA) patients and thereare promising preliminary results. The use ofPARP inhibitors in BRCA patients also repre-sents one of the fastest translations of a basicscience finding into clinical practice, providinga proof of principle for rational personalizedmedicine. The rapid advances in screen designand complementary technologies (e.g., single-molecule sequencing) provide hope that many

more success stories like this will follow in thenear future.

REFERENCES�Reference is also in this collection.

� Ashworth A, Bernards R. 2011. Using functional genetics tounderstand breast cancer biology. Cold Spring Harb Per-spect Biol doi: 10.1101/cshperspect.a003327.

Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Rich-ardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C,et al. 2005. Targeting the DNA repair defect in BRCA mu-tant cells as a therapeutic strategy. Nature 434: 917–921.

K. Polyak

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