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

Cell
Richard MarcotteBenjamin G Neel

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.

References

Jan 31, 1995·Proceedings of the National Academy of Sciences of the United States of America·J M BosherH C Hurst
Feb 3, 2000·Proceedings of the National Academy of Sciences of the United States of America·G M PaoI M Verma
Sep 13, 2001·Proceedings of the National Academy of Sciences of the United States of America·T SørlieA L Børresen-Dale
Oct 18, 2002·The European Journal of Neuroscience·Makoto TakemotoNobuhiko Yamamoto
Sep 11, 2007·Nature Methods·Renate KönigSumit K Chanda
Feb 11, 2009·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Joel S ParkerPhilip S Bernard
Jul 14, 2009·Breast Cancer Research and Treatment·Antoinette HollestelleMieke Schutte
Aug 12, 2009·Proceedings of the National Academy of Sciences of the United States of America·Chad J CreightonJenny C Chang
Sep 4, 2010·Breast Cancer Research : BCR·Aleix PratCharles M Perou
Jun 3, 2011·The Journal of Clinical Investigation·Brian D LehmannJennifer A Pietenpol
Mar 6, 2012·Cell·Wenjun GuoRobert A Weinberg
Apr 3, 2012·Cell·Chi V Dang
May 16, 2012·Cancer Discovery·Richard MarcotteJason Moffat
May 26, 2012·Science·Nicole L SoliminiStephen J Elledge
Jul 4, 2012·Molecular Cancer Therapeutics·Yongli GuoEthan Dmitrovsky
Aug 21, 2012·Cell·Deepak NijhawanWilliam C Hahn
Apr 24, 2013·Cell Research·Karin Flick, Peter Kaiser
Oct 15, 2013·Nature Methods·Malachi GriffithRichard K Wilson
Nov 2, 2013·Genome Biology·Anneleen DaemenJoe W Gray
Apr 30, 2014·Communicative & Integrative Biology·Pablo Garcia-Junco-Clemente, Peyman Golshani
Jun 7, 2014·Molecular Cell·Junwei Shi, Christopher R Vakoc
Jun 7, 2014·Annual Review of Biochemistry·Carolyn A Worby, Jack E Dixon
Mar 21, 2015·Drugs·Sohita Dhillon
Apr 17, 2015·Nature Communications·Venturina StagniDaniela Barilà
Jun 5, 2015·British Journal of Pharmacology·Vinayak S JamdadeNeeraj Sinha

❮ Previous
Next ❯

Citations

Mar 5, 2016·Cell Cycle·Xing Guo, Jack E Dixon
Apr 22, 2016·Nucleic Acids Research·Jüri ReimandJaak Vilo
Jun 9, 2016·Proceedings of the National Academy of Sciences of the United States of America·Kanak RainaKevin G Coleman
Jun 28, 2016·Cell Reports·Chi-Yeh ChungEmily Bernstein
Jul 20, 2016·Proceedings of the National Academy of Sciences of the United States of America·Xiarong ShiDavid A Calderwood
Oct 23, 2016·Drug Discovery Today. Technologies·Cheng-Ming Chiang
Sep 10, 2016·Breast Cancer Research : BCR·Bethany N HannafonW Q Ding
Nov 10, 2016·International Journal of Molecular Sciences·Yasushi Taniguchi
May 5, 2017·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Ashwani K SoodJessica Young
Jun 19, 2017·Molecular and Cellular Endocrinology·Alfonso Urbanucci, Ian G Mills
Jun 29, 2017·International Journal of Molecular Sciences·Sylvain LecomteFarzad Pakdel
Oct 28, 2017·Nucleic Acids Research·Walter F LenoirTraver Hart
Mar 24, 2018·Breast Cancer Research : BCR·Yew Chung TangSteven G Rozen
Oct 19, 2017·Cancer Metastasis Reviews·Yulin ChenXing Guo
Aug 31, 2016·Nature Methods·Lina WadiJüri Reimand
Mar 12, 2016·Arteriosclerosis, Thrombosis, and Vascular Biology·Yuqi ZhaoXia Yang
May 3, 2016·F1000Research·Gustavo Baldassarre, Barbara Belletti
Feb 6, 2019·International Journal of Molecular Sciences·Sarah AlexandrouC Elizabeth Caldon
Feb 8, 2018·Scientific Reports·Kittima AmornwachirabodeeSupason Wanichwecharungruang
Jun 28, 2019·PLoS Computational Biology·Sid KiblawiMark Craven
Dec 28, 2018·Cancer Research and Treatment : Official Journal of Korean Cancer Association·Juan ZhouSan-Gang Wu
Mar 13, 2019·Molecular Systems Biology·Avinash Das SahuEytan Ruppin
Nov 13, 2019·Molecular Carcinogenesis·Xuelu LiMan Li
Jun 11, 2016·Oncotarget·Vaibhav SahaiHidayatullah G Munshi

❮ Previous
Next ❯

Related Concepts

Related Feeds

AKT Pathway

This feed focuses on the AKT serine/threonine kinase, which is an important signaling pathway involved in processes such as glucose metabolism and cell survival.

Cell eTOC

Cell is a scientific journal publishing research across a broad range of disciplines within the life sciences field. Discover the latest research from Cell here.

Cancer Genomics (Keystone)

Cancer genomics approaches employ high-throughput technologies to identify the complete catalog of somatic alterations that characterize the genome, transcriptome and epigenome of cohorts of tumor samples. Discover the latest research using such technologies in this feed.