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PMID: 26771497 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Functional Genomic Landscape of Human Breast Cancer Drivers, Vulnerabilities, and Resistance.

Cell ·Vol. 164 ·No. 1-2 ·2016-01-14 ·Pages 293-309

Marcotte R, Sayad A, Brown KR, Sanchez-Garcia F, Reimand J, Haider M, Virtanen C, Bradner JE, Bader GD, Mills GB, Pe'er D, Moffat J, Neel BG

Abstract

Large-scale genomic studies have identified multiple somatic aberrations in breast cancer, including copy number alterations and point mutations. Still, identifying causal variants and emergent vulnerabilities that arise as a consequence of genetic alterations remain major challenges. We performed whole-genome small hairpin RNA (shRNA) "dropout screens" on 77 breast cancer cell lines. Using a hierarchical linear regression algorithm to score our screen results and integrate them with accompanying detailed genetic and proteomic information, we identify vulnerabilities in breast cancer, including candidate "drivers," and reveal general functional genomic properties of cancer cells. Comparisons of gene essentiality with drug sensitivity data suggest potential resistance mechanisms, effects of existing anti-cancer drugs, and opportunities for combination therapy. Finally, we demonstrate the utility of this large dataset by identifying BRD4 as a potential target in luminal breast cancer and PIK3CA mutations as a resistance determinant for BET-inhibitors.

MeSH Terms
Algorithms Breast Neoplasms/drug therapy,genetics,pathology Cell Cycle Proteins Cell Line, Tumor Class I Phosphatidylinositol 3-Kinases Cluster Analysis Drug Resistance, Neoplasm Gene Dosage Gene Expression Profiling Genome-Wide Association Study Humans Linear Models Nuclear Proteins/genetics Phosphatidylinositol 3-Kinases Transcription Factors/genetics
Chemicals
BRD4 protein, human Cell Cycle Proteins Nuclear Proteins Transcription Factors Class I Phosphatidylinositol 3-Kinases PIK3CA protein, human
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Marcotte Richard
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
Sayad Azin
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
Brown Kevin R
The Donnelly Centre, University of Toronto, ON M5S 3E1, Canada.
Sanchez-Garcia Felix
Columbia University, New York, NY 10027, USA.
Reimand Jüri
The Donnelly Centre, University of Toronto, ON M5S 3E1, Canada.
Haider Maliha
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
Virtanen Carl
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
Bradner James E
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
Bader Gary D
The Donnelly Centre, University of Toronto, ON M5S 3E1, Canada.
Mills Gordon B
Department of Systems Biology, Sheikh Khalifa Al Nahyan Ben Zayed Institute for Personalized Cancer Therapy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Pe'er Dana
Columbia University, New York, NY 10027, USA.
Moffat Jason
The Donnelly Centre, University of Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, ON M5S 3E1, Canada.
Neel Benjamin G
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Laura and Isaac Perlmutter Cancer Centre, NYU-Langone Medical Center, NY 10016, USA. Electronic address: benjamin.neel@nyumc.org.
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2015.11.062
Email
benjamin.neel@nyumc.org
Published
2016-01-14
Pages
293-309
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC4724865
Subset
IM
Grants
NCI NIH HHS · R01 CA164729 · United States
NCI NIH HHS · R37 CA49132 · United States
NCI NIH HHS · P30 CA016672 · United States
NHGRI NIH HHS · U41 HG006623 · United States
NCI NIH HHS · CA16672 · United States
NIGMS NIH HHS · P41 GM103504 · United States
NCI NIH HHS · R01 CA049152 · United States
NCI NIH HHS · P01 CA099031 · United States
NIGMS NIH HHS · R01 GM070743 · United States
External Links
PubMed source DOI: 10.1016/j.cell.2015.11.062 PMC Full Text View journal details
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