TY - JOUR
T1 - Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
AU - Langille, Ellen
AU - Al-Zahrani, Khalid N.
AU - Ma, Zhibo
AU - Liang, Minggao
AU - Uuskula-Reimand, Liis
AU - Espin, Roderic
AU - Teng, Katie
AU - Malik, Ahmad
AU - Bergholtz, Helga
AU - El Ghamrasni, Samah
AU - Afiuni-Zadeh, Somaieh
AU - Tsai, Ricky
AU - Alvi, Sana
AU - Elia, Andrew
AU - Lü, Yiqing
AU - Oh, Robin H.
AU - Kozma, Katelyn J.
AU - Trcka, Daniel
AU - Narimatsu, Masahiro
AU - Liu, Jeff C.
AU - Nguyen, Thomas
AU - Barutcu, Seda
AU - Loganathan, Sampath K.
AU - Bremner, Rod
AU - Bader, Gary D.
AU - Egan, Sean E.
AU - Cescon, David W.
AU - Sørlie, Therese
AU - Wrana, Jeffrey L.
AU - Jackson, Hartland W.
AU - Wilson, Michael D.
AU - Witkiewicz, Agnieszka K.
AU - Knudsen, Erik S.
AU - Pujana, Miguel Angel
AU - Wahl, Geoffrey M.
AU - Schramek, Daniel
N1 - Funding Information:
We thank all members of our laboratories for helpful comments, with additional thanks to K. Schleicher, and G. Mbamalu for their insight and assistance. We thank H. Melo and D. Durocher for assistance with the visualization of g:Profiler data. We also thank the Centre for Phenogenomics, Network Biology Collaborative Centre, and Flow Cytometry Facility at the Lunenfeld-Tanenbaum Research Institute as well as the Flow Cytometry Facility at the University of Toronto. This work was supported by a Career Catalyst Research Grant to D. Schramek from the Susan G. Komen Foundation (CCR16377321), a Terry Fox Research Institute Program Projects Grant to J.L. Wrana and D. Schramek and colleagues (TFRI Project #1107), and by the Nicol Family Foundation. E. Langille is a recipient of the Ontario Graduate Scholarship and the Frank Fletcher Memorial Fund, K.N. Al-Zahrani is a recipient of the Medicine By Design fellowship and supported by a Sinai Health System Foundation donation (Mr. Ah Shai), S.K. Loganathan is a Canadian Cancer Society Fellowship recipient (BC-F-16#31919), and L. Uuskula-Reimand is a recipient of the Next Generation of Scientists Scholarship from the Cancer Research Society (PIN25558). G.M. Wahl and Z. Ma are supported by a Cancer Center Core Grant (5 P30CA014195), the NIH/ NCI (R35 CA197687), and the Breast Cancer Research Foundation. S.E. Egan is supported by the Canadian Institutes of Health Research. R. Espin and M.A. Pujana were supported by grants from the Carlos III Institute of Health (PI18/01029 and PI21/01306; cofunded by European Regional Development Fund, a way to build Europe), Generalitat de Catalunya (SGR 2017–449), and the CERCA Program to IDIBELL.
Funding Information:
We thank all members of our laboratories for helpful comments, with additional thanks to K. Schleicher, and G. Mbamalu for their insight and assistance. We thank H. Melo and D. Durocher for assistance with the visualization of g:Profiler data. We also thank the Centre for Phenogenomics, Network Biology Collaborative Centre, and Flow Cytometry Facility at the Lunenfeld-Tanenbaum Research Institute as well as the Flow Cytometry Facility at the University of Toronto. This work was supported by a Career Catalyst Research Grant to D. Schramek from the Susan G. Komen Foundation (CCR16377321), a Terry Fox Research Institute Program Projects Grant to J.L. Wrana and D. Schramek and colleagues (TFRI Project #1107), and by the Nicol Family Foundation. E. Langille is a recipient of the Ontario Graduate Scholarship and the Frank Fletcher Memorial Fund, K.N. Al-Zahrani is a recipient of the Medicine By Design fellowship and supported by a Sinai Health System Foundation dona-tion (Mr. Ah Shai), S.K. Loganathan is a Canadian Cancer Society Fellowship recipient (BC-F-16#31919), and L. Uuskula-Reimand is a recipient of the Next Generation of Scientists Scholarship from the Cancer Research Society (PIN25558). G.M. Wahl and Z. Ma are supported by a Cancer Center Core Grant (5 P30CA014195), the NIH/ NCI (R35 CA197687), and the Breast Cancer Research Foundation. S.E. Egan is supported by the Canadian Institutes of Health Research. R. Espin and M.A. Pujana were supported by grants from the Carlos III Institute of Health (PI18/01029 and PI21/01306; cofunded by Euro-pean Regional Development Fund, a way to build Europe), Generalitat de Catalunya (SGR 2017–449), and the CERCA Program to IDIBELL. The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.
Publisher Copyright:
© 2022 American Association for Cancer Research.
PY - 2022/12/1
Y1 - 2022/12/1
N2 - Systematically investigating the scores of genes mutated in cancer and discerning disease drivers from inconsequential bystanders is a prerequisite for precision medicine but remains challenging. Here, we developed a somatic CRISPR/Cas9 mutagenesis screen to study 215 recurrent “long-tail” breast cancer genes, which revealed epigenetic regulation as a major tumor-suppressive mechanism. We report that components of the BAP1 and COMPASS-like com-plexes, including KMT2C/D, KDM6A, BAP1, and ASXL1/2 (“EpiDrivers”), cooperate with PIK3CAH1047R to transform mouse and human breast epithelial cells. Mechanistically, we find that activation of PIK3CAH1047R and concomitant EpiDriver loss triggered an alveolar-like lineage conversion of basal mammary epithelial cells and accelerated formation of luminal-like tumors, suggesting a basal origin for luminal tumors. EpiDriver mutations are found in ∼39% of human breast cancers, and ∼50% of ductal carcinoma in situ express casein, suggesting that lineage infidelity and alveogenic mimicry may significantly contribute to early steps of breast cancer etiology. SIGNIFICANCE: Infrequently mutated genes comprise most of the mutational burden in breast tumors but are poorly understood. In vivo CRISPR screening identified functional tumor suppressors that converged on epigenetic regulation. Loss of epigenetic regulators accelerated tumorigenesis and revealed lineage infidelity and aberrant expression of alveogenesis genes as potential early events in tumorigenesis.
AB - Systematically investigating the scores of genes mutated in cancer and discerning disease drivers from inconsequential bystanders is a prerequisite for precision medicine but remains challenging. Here, we developed a somatic CRISPR/Cas9 mutagenesis screen to study 215 recurrent “long-tail” breast cancer genes, which revealed epigenetic regulation as a major tumor-suppressive mechanism. We report that components of the BAP1 and COMPASS-like com-plexes, including KMT2C/D, KDM6A, BAP1, and ASXL1/2 (“EpiDrivers”), cooperate with PIK3CAH1047R to transform mouse and human breast epithelial cells. Mechanistically, we find that activation of PIK3CAH1047R and concomitant EpiDriver loss triggered an alveolar-like lineage conversion of basal mammary epithelial cells and accelerated formation of luminal-like tumors, suggesting a basal origin for luminal tumors. EpiDriver mutations are found in ∼39% of human breast cancers, and ∼50% of ductal carcinoma in situ express casein, suggesting that lineage infidelity and alveogenic mimicry may significantly contribute to early steps of breast cancer etiology. SIGNIFICANCE: Infrequently mutated genes comprise most of the mutational burden in breast tumors but are poorly understood. In vivo CRISPR screening identified functional tumor suppressors that converged on epigenetic regulation. Loss of epigenetic regulators accelerated tumorigenesis and revealed lineage infidelity and aberrant expression of alveogenesis genes as potential early events in tumorigenesis.
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U2 - 10.1158/2159-8290.CD-21-0865
DO - 10.1158/2159-8290.CD-21-0865
M3 - Article
C2 - 36108220
AN - SCOPUS:85143200607
SN - 2159-8274
VL - 12
SP - 2930
EP - 2953
JO - Cancer Discovery
JF - Cancer Discovery
IS - 12
ER -