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1.
Cancer Discov ; 12(12): 2930-2953, 2022 12 02.
Article in English | MEDLINE | ID: mdl-36108220

ABSTRACT

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 complexes, 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. This article is highlighted in the In This Issue feature, p. 2711.


Subject(s)
Breast Neoplasms , Carcinoma, Intraductal, Noninfiltrating , Humans , Mice , Animals , Female , Breast Neoplasms/pathology , Epigenesis, Genetic , Neoplasm Recurrence, Local/genetics , Carcinoma, Intraductal, Noninfiltrating/genetics , Cell Transformation, Neoplastic/genetics
2.
Nat Commun ; 12(1): 5238, 2021 09 02.
Article in English | MEDLINE | ID: mdl-34475389

ABSTRACT

The most common events in breast cancer (BC) involve chromosome arm losses and gains. Here we describe identification of 1089 gene-centric common insertion sites (gCIS) from transposon-based screens in 8 mouse models of BC. Some gCIS are driver-specific, others driver non-specific, and still others associated with tumor histology. Processes affected by driver-specific and histology-specific mutations include well-known cancer pathways. Driver non-specific gCIS target the Mediator complex, Ca++ signaling, Cyclin D turnover, RNA-metabolism among other processes. Most gCIS show single allele disruption and many map to genomic regions showing high-frequency hemizygous loss in human BC. Two gCIS, Nf1 and Trps1, show synthetic haploinsufficient tumor suppressor activity. Many gCIS act on the same pathway responsible for tumor initiation, thereby selecting and sculpting just enough and just right signaling. These data highlight ~1000 genes with predicted conditional haploinsufficient tumor suppressor function and the potential to promote chromosome arm loss in BC.


Subject(s)
Breast Neoplasms/genetics , Loss of Heterozygosity/genetics , Animals , Breast Neoplasms/pathology , Cell Transformation, Neoplastic , DNA Transposable Elements/genetics , Female , Genes, Tumor Suppressor , Humans , Mice , Mutagenesis, Insertional , Neoplasms, Experimental , Signal Transduction
3.
EMBO Mol Med ; 13(3): e13807, 2021 03 05.
Article in English | MEDLINE | ID: mdl-33616312

ABSTRACT

Invasive lobular carcinoma (ILC) of the breast is a very common disease. Despite its prevalence, these tumors are relatively understudied. One reason for this is a relative lack of models for ILC. This challenge was addressed by Brisken and colleagues through development of an intraductal injection-based xenograft system for the study of ERα+ breast cancers, including both ILC and more common invasive ductal carcinoma (IDC; Sflomos et al, 2016). In this issue of EMBO Molecular Medicine, the same group have applied intraductal injection-based xenografts to identify novel tumor cell-specific transcriptional signatures in ILC (Sflomos et al, 2021). In doing so they found overexpression of lysyl oxidase-like 1 (LOXL1) to be both responsible for the frequently seen stiff collagen-rich extracellular matrix of lobular breast cancer and essential for their robust growth and metastatic dissemination in vivo, thereby identifying a novel therapeutic target.


Subject(s)
Breast Neoplasms , Carcinoma, Ductal, Breast , Carcinoma, Lobular , Breast , Female , Humans , Retrospective Studies
4.
Cell Rep ; 25(3): 702-714.e6, 2018 10 16.
Article in English | MEDLINE | ID: mdl-30332649

ABSTRACT

CDH1 and PIK3CA are the two most frequently mutated genes in invasive lobular carcinoma (ILC) of the breast. Transcription profiling has identified molecular subtypes for ILC, one of which, immune-related (IR), is associated with gene expression linked to lymphocyte and macrophage infiltration. Here, we report that deletion of Cdh1, together with activation of Pik3ca in mammary epithelium of genetically modified mice, leads to formation of IR-ILC-like tumors with immune cell infiltration, as well as gene expression linked to T-regulatory (Treg) cell signaling and activation of targetable immune checkpoint pathways. Interestingly, these tumors show enhanced Rac1- and Yap-dependent transcription and signaling, as well as sensitivity to PI3K, Rac1, and Yap inhibitors in culture. Finally, high-dimensional immunophenotyping in control mouse mammary gland and IR-ILC tumors by mass cytometry shows dramatic alterations in myeloid and lymphoid populations associated with immune suppression and exhaustion, highlighting the potential for therapeutic intervention via immune checkpoint regulators.


Subject(s)
Cadherins/physiology , Carcinoma, Lobular/pathology , Gene Expression Regulation, Neoplastic , Mammary Neoplasms, Animal/pathology , Mutation , Phosphatidylinositol 3-Kinases/physiology , Adaptor Proteins, Signal Transducing/metabolism , Animals , Carcinoma, Lobular/immunology , Carcinoma, Lobular/metabolism , Cell Cycle Proteins/metabolism , Class I Phosphatidylinositol 3-Kinases , Female , Mammary Neoplasms, Animal/immunology , Mammary Neoplasms, Animal/metabolism , Mice , Mice, Knockout , Myeloid Cells/immunology , Myeloid Cells/metabolism , Myeloid Cells/pathology , Neoplasm Invasiveness , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , T-Lymphocytes/pathology , Transcriptome , YAP-Signaling Proteins , rac GTP-Binding Proteins/metabolism
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