Mammary molecular portraits reveal lineage-specific features and progenitor cell vulnerabilities

被引：27

作者：

Casey, Alison E. ^{[1
]}

Sinha, Ankit ^{[1
]}

Singhania, Rajat ^{[1
]}

Livingstone, Julie ^{[2
]}

Waterhouse, Paul ^{[1
]}

Tharmapalan, Pirashaanthy ^{[1
]}

Cruickshank, Jennifer ^{[1
]}

Shehata, Mona ^{[1
]}

Drysdale, Erik ^{[2
]}

Fang, Hui ^{[1
]}

Kim, Hyeyeon ^{[1
]}

Isserlin, Ruth ^{[3
]}

Bailey, Swneke ^{[1
]}

Medina, Tiago ^{[1
]}

Deblois, Genevieve ^{[1
]}

Shiah, Yu-Jia ^{[2
]}

Barsyte-Lovejoy, Dalia ^{[4
]}

Hofer, Stefan ^{[1
]}

Bader, Gary ^{[3
]}

Lupien, Mathieu ^{[1
,6
]}

Arrowsmith, Cheryl ^{[1
,4
,6
]}

Knapp, Stefan ^{[5
]}

De Carvalho, Daniel ^{[1
,6
]}

Berman, Hal ^{[1
,8
]}

Boutros, Paul C. ^{[2
,6
,7
]}

Kislinger, Thomas ^{[1
,6
]}

Khokha, Rama ^{[1
,6
]}

机构：

[1] Princess Margaret Canc Ctr, Toronto, ON, Canada

[2] Ontario Inst Canc Res, Informat & Biocomp Program, Toronto, ON, Canada

[3] Univ Toronto, Donnelly Ctr, Toronto, ON, Canada

[4] Univ Toronto, Struct Genom Consortium, Toronto, ON, Canada

[5] Univ Oxford, Nuffield Dept Clin Med, Struct Genom Consortium, Oxford, England

[6] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada

[7] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON, Canada

[8] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada

来源：

JOURNAL OF CELL BIOLOGY | 2018年 / 217卷 / 08期

基金：

加拿大健康研究院;

关键词：

EPITHELIAL STEM-CELLS; BREAST-CANCER; FUNCTIONAL INTERPRETATION; EXPRESSION; BRCA1; MOUSE; RISK; GLAND; PROLIFERATION; EPIGENOME;

D O I：

10.1083/jcb.201804042

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The mammary epithelium depends on specific lineages and their stem and progenitor function to accommodate hormone-triggered physiological demands in the adult female. Perturbations of these lineages underpin breast cancer risk, yet our understanding of normal mammary cell composition is incomplete. Here, we build a multimodal resource for the adult gland through comprehensive profiling of primary cell epigenomes, transcriptomes, and proteomes. We define systems-level relationships between chromatin-DNA-RNA-protein states, identify lineage-specific DNA methylation of transcription factor binding sites, and pinpoint proteins underlying progesterone responsiveness. Comparative proteomics of estrogen and progesterone receptor-positive and -negative cell populations, extensive target validation, and drug testing lead to discovery of stem and progenitor cell vulnerabilities. Top epigenetic drugs exert cytostatic effects; prevent adult mammary cell expansion, clonogenicity, and mammopoiesis; and deplete stem cell frequency. Select drugs also abrogate human breast progenitor cell activity in normal and high-risk patient samples. This integrative computational and functional study provides fundamental insight into mammary lineage and stem cell biology.

引用

页码：2951 / 2974

页数：24

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