title: Functional Genomic Landscape of Human Breast Cancer Drivers, Vulnerabilities, and Resistance.
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.
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Marcotte
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Azin
authors.initials: A
authors.lastname: Sayad
authors.affiliation: The Donnelly Centre, University of Toronto, ON M5S 3E1, Canada.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Brown
authors.affiliation: Columbia University, New York, NY 10027, USA.
authors.forename: Felix
authors.initials: F
authors.lastname: Sanchez-Garcia
authors.affiliation: The Donnelly Centre, University of Toronto, ON M5S 3E1, Canada.
authors.forename: Jüri
authors.initials: J
authors.lastname: Reimand
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Maliha
authors.initials: M
authors.lastname: Haider
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Carl
authors.initials: C
authors.lastname: Virtanen
authors.affiliation: 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.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: The Donnelly Centre, University of Toronto, ON M5S 3E1, Canada.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Bader
authors.affiliation: 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.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Columbia University, New York, NY 10027, USA.
authors.forename: Dana
authors.initials: D
authors.lastname: Pe'er
authors.affiliation: The Donnelly Centre, University of Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, ON M5S 3E1, Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: Moffat
authors.affiliation: 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.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Neel
mesh_terms: D000465:Algorithms; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm; D018628:Gene Dosage; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D006801:Humans; D016014:Linear Models; D009687:Nuclear Proteins / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases; D014157:Transcription Factors / Q000235:genetics; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D058534:Class I Phosphatidylinositol 3-Kinases; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C484760:PIK3CA protein, human