Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer

Ellen Langille, Khalid N. Al-Zahrani, Zhibo Ma, Minggao Liang, Liis Uuskula-Reimand, Roderic Espin, Katie Teng, Ahmad Malik, Helga Bergholtz, Samah El Ghamrasni, Somaieh Afiuni-Zadeh, Ricky Tsai, Sana Alvi, Andrew Elia, Yiqing Lü, Robin H. Oh, Katelyn J. Kozma, Daniel Trcka, Masahiro Narimatsu, Jeff C. LiuThomas Nguyen, Seda Barutcu, Sampath K. Loganathan, Rod Bremner, Gary D. Bader, Sean E. Egan, David W. Cescon, Therese Sørlie, Jeffrey L. Wrana, Hartland W. Jackson, Michael D. Wilson, Agnieszka K. Witkiewicz, Erik S. Knudsen, Miguel Angel Pujana, Geoffrey M. Wahl, Daniel Schramek

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2930-2953
Number of pages24
JournalCancer discovery
Issue number12
StatePublished - Dec 1 2022
Externally publishedYes

ASJC Scopus subject areas

  • Oncology


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