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 - 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 -