Barbara Vivash Award Seminar: Dr. Ellen Langille
Barbara Vivash Award Seminar
Departmental Seminar Series & Award Presentation
2022/2023 Recipient: Ellen Langille, PhD
Affiliation: Sinai Health | Lunenfeld-Tanenbaum Research Institute
MoGen PhD Supervisor: Dr. Daniel Schramek
Location: Donnelly Centre, Red Room
Date: Monday, October 7th , 2024 at 3:00 PM
In vivo screening for regulation of mammary tumour initiation
There are hundreds of genes mutated in breast cancer, but identification of functional driver mutations from among inconsequential bystanders remains challenging. We performed 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 identified that components of the BAP1 and the COMPASS-like complexes, including KDM6A, BAP1, ASXL1/2, and KMT2C/D, cooperate with PIK3CAH1047R to transform mouse and human breast epithelial cells. Mechanistically, we found that activation of PIK3CAH1047R and concomitant loss of epigenetic regulation triggered an alveolar-like lineage conversion of basal mammary epithelial cells and accelerated formation of luminal-like tumors. Mutations in epigenetic regulators are found in >39% of human breast cancers and milk protein expression can be seen in ~50% of ductal-carcinoma-in-situ, suggesting that lineage infidelity and alveolar mimicry may significantly contribute to breast cancer initiation.