Aneuploidy and a Deregulated DNA Damage Response Suggest Haploinsufficiency in Breast Tissues of Mutation Carriers

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2020 Feb 18

PMID 32064343

Citations 21

Authors

Mihriban Karaayvaz-Yildirim

Rebecca E Silberman

Adam Langenbucher

Srinivas Vinod Saladi

Kenneth N Ross

Elena Zarcaro

Andrea Desmond

Murat Yildirim

Varunika Vivekanandan

Hiranmayi Ravichandran

Ravindra Mylavagnanam

Michelle C Specht

Sridhar Ramaswamy

Michael Lawrence

Angelika Amon

Leif W Ellisen

Affiliations

Soon will be listed here.

Abstract

Women harboring heterozygous germline mutations of have a 50 to 80% risk of developing breast cancer, yet the pathogenesis of these cancers is poorly understood. To reveal early steps in -associated carcinogenesis, we analyzed sorted cell populations from freshly-isolated, non-cancerous breast tissues of mutation carriers and matched controls. Single-cell whole-genome sequencing demonstrates that >25% of carrier ( ) luminal progenitor (LP) cells exhibit sub-chromosomal copy number variations, which are rarely observed in non-carriers. Correspondingly, primary breast epithelia exhibit DNA damage together with attenuated replication checkpoint and apoptotic responses, and an age-associated expansion of the LP compartment. We provide evidence that these phenotypes do not require loss of the wild-type allele. Collectively, our findings suggest that haploinsufficiency and associated DNA damage precede histologic abnormalities in vivo. Using these hallmarks of cancer predisposition will yield unanticipated opportunities for improved risk assessment and prevention strategies in high-risk patients.

Citing Articles

Cells-of-Origin of Breast Cancer and Intertumoral Heterogeneity.

Joyce R, Visvader J Adv Exp Med Biol. 2025; 1464():151-165.

PMID: 39821025 DOI: 10.1007/978-3-031-70875-6_9.

Normal breast tissues harbour rare populations of aneuploid epithelial cells.

Lin Y, Wang J, Wang K, Bai S, Thennavan A, Wei R Nature. 2024; 636(8043):663-670.

PMID: 39567687 DOI: 10.1038/s41586-024-08129-x.

BRCA1 and BRCA2: from cancer susceptibility to synthetic lethality.

Khalizieva A, Moser S, Bouwman P, Jonkers J Genes Dev. 2024; 39(1-2):86-108.

PMID: 39510841 PMC: 11789497. DOI: 10.1101/gad.352083.124.

PALB2-mutated human mammary cells display a broad spectrum of morphological and functional abnormalities induced by increased TGFβ signaling.

Tuppurainen H, Laurila N, Natynki M, Eshraghi L, Tervasmaki A, Erichsen L Cell Mol Life Sci. 2024; 81(1):173.

PMID: 38597967 PMC: 11006627. DOI: 10.1007/s00018-024-05183-6.

BRCA2 promotes genomic integrity and therapy resistance primarily through its role in homology-directed repair.

Lim P, Zaman M, Feng W, Jasin M Mol Cell. 2024; 84(3):447-462.e10.

PMID: 38244544 PMC: 11188060. DOI: 10.1016/j.molcel.2023.12.025.

References

Ghandhi S, Yaghoubian B, Amundson S . Global gene expression analyses of bystander and alpha particle irradiated normal human lung fibroblasts: synchronous and differential responses. BMC Med Genomics. 2008; 1:63. PMC: 2627914. DOI: 10.1186/1755-8794-1-63. View

Younger S, Kenzelmann-Broz D, Jung H, Attardi L, Rinn J . Integrative genomic analysis reveals widespread enhancer regulation by p53 in response to DNA damage. Nucleic Acids Res. 2015; 43(9):4447-62. PMC: 4482066. DOI: 10.1093/nar/gkv284. View

Kastan M, Bartek J . Cell-cycle checkpoints and cancer. Nature. 2004; 432(7015):316-23. DOI: 10.1038/nature03097. View

Sieben C, Sturmlechner I, van de Sluis B, van Deursen J . Two-Step Senescence-Focused Cancer Therapies. Trends Cell Biol. 2018; 28(9):723-737. PMC: 6102047. DOI: 10.1016/j.tcb.2018.04.006. View

Feuerhake F, Sigg W, Hofter E, Unterberger P, Welsch U . Cell proliferation, apoptosis, and expression of Bcl-2 and Bax in non-lactating human breast epithelium in relation to the menstrual cycle and reproductive history. Breast Cancer Res Treat. 2003; 77(1):37-48. DOI: 10.1023/a:1021119830269. View

Gowen L, Johnson B, Latour A, Sulik K, Koller B . Brca1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities. Nat Genet. 1996; 12(2):191-4. DOI: 10.1038/ng0296-191. View

. Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Breast Cancer Linkage Consortium. Lancet. 1997; 349(9064):1505-10. View

Tan S, Chadha S, Liu Y, Gabasova E, Perera D, Ahmed K . A Class of Environmental and Endogenous Toxins Induces BRCA2 Haploinsufficiency and Genome Instability. Cell. 2017; 169(6):1105-1118.e15. PMC: 5457488. DOI: 10.1016/j.cell.2017.05.010. View

Veuger S, Durkacz B . Persistence of unrepaired DNA double strand breaks caused by inhibition of ATM does not lead to radio-sensitisation in the absence of NF-κB activation. DNA Repair (Amst). 2010; 10(2):235-44. DOI: 10.1016/j.dnarep.2010.11.005. View

10.

Robert N, Tremblay J, Viger R . Friend of GATA (FOG)-1 and FOG-2 differentially repress the GATA-dependent activity of multiple gonadal promoters. Endocrinology. 2002; 143(10):3963-73. DOI: 10.1210/en.2002-220280. View

11.

Hakem R, de la Pompa J, Sirard C, Mo R, Woo M, Hakem A . The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse. Cell. 1996; 85(7):1009-23. DOI: 10.1016/s0092-8674(00)81302-1. View

12.

Feng W, Jasin M . Homologous Recombination and Replication Fork Protection: BRCA2 and More!. Cold Spring Harb Symp Quant Biol. 2018; 82:329-338. PMC: 6333483. DOI: 10.1101/sqb.2017.82.035006. View

13.

Knouse K, Wu J, Amon A . Assessment of megabase-scale somatic copy number variation using single-cell sequencing. Genome Res. 2016; 26(3):376-84. PMC: 4772019. DOI: 10.1101/gr.198937.115. View

14.

Ramsey M, Wilson C, Ory B, Rothenberg S, Faquin W, Mills A . FGFR2 signaling underlies p63 oncogenic function in squamous cell carcinoma. J Clin Invest. 2013; 123(8):3525-38. PMC: 3726171. DOI: 10.1172/JCI68899. View

15.

Davies H, Glodzik D, Morganella S, Yates L, Staaf J, Zou X . HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat Med. 2017; 23(4):517-525. PMC: 5833945. DOI: 10.1038/nm.4292. View

16.

Suzuki A, de la Pompa J, Hakem R, Elia A, Yoshida R, Mo R . Brca2 is required for embryonic cellular proliferation in the mouse. Genes Dev. 1997; 11(10):1242-52. DOI: 10.1101/gad.11.10.1242. View

17.

Nolan E, Vaillant F, Branstetter D, Pal B, Giner G, Whitehead L . RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers. Nat Med. 2016; 22(8):933-9. DOI: 10.1038/nm.4118. View

18.

Tutt A, Connor F, Bertwistle D, Kerr P, Peacock J, Ross G . Cell cycle and genetic background dependence of the effect of loss of BRCA2 on ionizing radiation sensitivity. Oncogene. 2003; 22(19):2926-31. DOI: 10.1038/sj.onc.1206522. View

19.

Jonkers J, Meuwissen R, van der Gulden H, Peterse H, van der Valk M, Berns A . Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat Genet. 2001; 29(4):418-25. DOI: 10.1038/ng747. View

20.

Maxwell K, Wubbenhorst B, Wenz B, De Sloover D, Pluta J, Emery L . BRCA locus-specific loss of heterozygosity in germline BRCA1 and BRCA2 carriers. Nat Commun. 2017; 8(1):319. PMC: 5567274. DOI: 10.1038/s41467-017-00388-9. View