@article{23845eb5da24480ea2e3c3ac91778d49,
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.",
author = "Richard Marcotte and Azin Sayad and Brown, {Kevin R.} and Felix Sanchez-Garcia and J{\"u}ri Reimand and Maliha Haider and Carl Virtanen and Bradner, {James E.} and Bader, {Gary D.} and Mills, {Gordon B.} and Dana Pe'Er and Jason Moffat and Neel, {Benjamin G.}",
note = "Funding Information: This work was supported by the Canadian Foundation for Innovation (J.M.) and the Ontario Research Fund (B.G.N. and J.M.). B.G.N. was a Canada Research Chair, Tier 1, and work in his laboratory was supported in part by the Princess Margaret Cancer Foundation. R.M. was partly funded by a postdoctoral fellowship from the Canadian Breast Cancer Foundation. This work was also supported by NIH grants R37 CA49132 (B.G.N.), P41 GM103504, R01 GM070743, U41 HG006623 (G.D.B.), and PO1 CA099031 (G.B.M.), a Komen SAC and Promise grant (G.B.M.), and the M.D. Anderson CCSG functional proteomics core (CA16672). Funding Information: This work was supported by the Canadian Foundation for Innovation (J.M.) and the Ontario Research Fund (B.G.N. and J.M.). B.G.N. was a Canada Research Chair, Tier 1, and work in his laboratory was supported in part by the Princess Margaret Cancer Foundation. R.M. was partly funded by a postdoctoral fellowship from the Canadian Breast Cancer Foundation. This work was also supported by NIH grants R37 CA49132 (B.G.N.), P41 GM103504, R01 GM070743, U41 HG006623 (G.D.B.), and PO1 CA099031 (G.B.M.), a Komen SAC and Promise grant (G.B.M.), and the M.D. Anderson CCSG functional proteomics core (CA16672). Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",
year = "2016",
month = jan,
day = "14",
doi = "10.1016/j.cell.2015.11.062",
language = "English (US)",
volume = "164",
pages = "293--309",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "1-2",
}