BRCA1 deficiency exacerbates estrogen-induced DNA damage and genomic instability

Kienan I Savage, Kyle B Matchett, Eliana M Barros, Kevin M Cooper, Gareth W Irwin, Julia J Gorski, Katy S Orr, Jekaterina Vohhodina, Joy N Kavanagh, Angelina F Madden, Alexander Powell, Lorenzo Manti, Simon S McDade, Ben Ho Park, Kevin M Prise, Stuart A McIntosh, Manuel Salto-Tellez, Derek J Richard, Christopher T Elliott, D Paul Harkin

Research output: Contribution to journalArticle

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Abstract

Germline mutations in BRCA1 predispose carriers to a high incidence of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through critical roles in DNA repair, cell-cycle arrest, and transcriptional control. A major question has been why BRCA1 loss or mutation leads to tumors mainly in estrogen-regulated tissues, given that BRCA1 has essential functions in all cell types. Here, we report that estrogen and estrogen metabolites can cause DNA double-strand breaks (DSB) in estrogen receptor-α-negative breast cells and that BRCA1 is required to repair these DSBs to prevent metabolite-induced genomic instability. We found that BRCA1 also regulates estrogen metabolism and metabolite-mediated DNA damage by repressing the transcription of estrogen-metabolizing enzymes, such as CYP1A1, in breast cells. Finally, we used a knock-in human cell model with a heterozygous BRCA1 pathogenic mutation to show how BRCA1 haploinsufficiency affects these processes. Our findings provide pivotal new insights into why BRCA1 mutation drives the formation of tumors in estrogen-regulated tissues, despite the general role of BRCA1 in DNA repair in all cell types.
LanguageEnglish
Pages2773-2784
Number of pages12
JournalCancer Research
Volume74
Issue number10
Publication statusPublished - 15 May 2014

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Genomic Instability
DNA Damage
Estrogens
DNA Repair
Mutation
Breast
Haploinsufficiency
Cytochrome P-450 CYP1A1
Double-Stranded DNA Breaks
Estrogen Receptor alpha
Germ-Line Mutation
Cell Cycle Checkpoints
Ovarian Neoplasms
Neoplasms
Breast Neoplasms
Incidence
Enzymes

Cite this

Savage, K. I., Matchett, K. B., Barros, E. M., Cooper, K. M., Irwin, G. W., Gorski, J. J., ... Harkin, D. P. (2014). BRCA1 deficiency exacerbates estrogen-induced DNA damage and genomic instability. Cancer Research, 74(10), 2773-2784.
Savage, Kienan I ; Matchett, Kyle B ; Barros, Eliana M ; Cooper, Kevin M ; Irwin, Gareth W ; Gorski, Julia J ; Orr, Katy S ; Vohhodina, Jekaterina ; Kavanagh, Joy N ; Madden, Angelina F ; Powell, Alexander ; Manti, Lorenzo ; McDade, Simon S ; Ho Park, Ben ; Prise, Kevin M ; McIntosh, Stuart A ; Salto-Tellez, Manuel ; Richard, Derek J ; Elliott, Christopher T ; Harkin, D Paul. / BRCA1 deficiency exacerbates estrogen-induced DNA damage and genomic instability. In: Cancer Research. 2014 ; Vol. 74, No. 10. pp. 2773-2784.
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title = "BRCA1 deficiency exacerbates estrogen-induced DNA damage and genomic instability",
abstract = "Germline mutations in BRCA1 predispose carriers to a high incidence of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through critical roles in DNA repair, cell-cycle arrest, and transcriptional control. A major question has been why BRCA1 loss or mutation leads to tumors mainly in estrogen-regulated tissues, given that BRCA1 has essential functions in all cell types. Here, we report that estrogen and estrogen metabolites can cause DNA double-strand breaks (DSB) in estrogen receptor-α-negative breast cells and that BRCA1 is required to repair these DSBs to prevent metabolite-induced genomic instability. We found that BRCA1 also regulates estrogen metabolism and metabolite-mediated DNA damage by repressing the transcription of estrogen-metabolizing enzymes, such as CYP1A1, in breast cells. Finally, we used a knock-in human cell model with a heterozygous BRCA1 pathogenic mutation to show how BRCA1 haploinsufficiency affects these processes. Our findings provide pivotal new insights into why BRCA1 mutation drives the formation of tumors in estrogen-regulated tissues, despite the general role of BRCA1 in DNA repair in all cell types.",
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Savage, KI, Matchett, KB, Barros, EM, Cooper, KM, Irwin, GW, Gorski, JJ, Orr, KS, Vohhodina, J, Kavanagh, JN, Madden, AF, Powell, A, Manti, L, McDade, SS, Ho Park, B, Prise, KM, McIntosh, SA, Salto-Tellez, M, Richard, DJ, Elliott, CT & Harkin, DP 2014, 'BRCA1 deficiency exacerbates estrogen-induced DNA damage and genomic instability', Cancer Research, vol. 74, no. 10, pp. 2773-2784.

BRCA1 deficiency exacerbates estrogen-induced DNA damage and genomic instability. / Savage, Kienan I; Matchett, Kyle B; Barros, Eliana M; Cooper, Kevin M; Irwin, Gareth W; Gorski, Julia J; Orr, Katy S; Vohhodina, Jekaterina; Kavanagh, Joy N; Madden, Angelina F; Powell, Alexander; Manti, Lorenzo; McDade, Simon S; Ho Park, Ben; Prise, Kevin M; McIntosh, Stuart A; Salto-Tellez, Manuel; Richard, Derek J; Elliott, Christopher T; Harkin, D Paul.

In: Cancer Research, Vol. 74, No. 10, 15.05.2014, p. 2773-2784.

Research output: Contribution to journalArticle

TY - JOUR

T1 - BRCA1 deficiency exacerbates estrogen-induced DNA damage and genomic instability

AU - Savage, Kienan I

AU - Matchett, Kyle B

AU - Barros, Eliana M

AU - Cooper, Kevin M

AU - Irwin, Gareth W

AU - Gorski, Julia J

AU - Orr, Katy S

AU - Vohhodina, Jekaterina

AU - Kavanagh, Joy N

AU - Madden, Angelina F

AU - Powell, Alexander

AU - Manti, Lorenzo

AU - McDade, Simon S

AU - Ho Park, Ben

AU - Prise, Kevin M

AU - McIntosh, Stuart A

AU - Salto-Tellez, Manuel

AU - Richard, Derek J

AU - Elliott, Christopher T

AU - Harkin, D Paul

PY - 2014/5/15

Y1 - 2014/5/15

N2 - Germline mutations in BRCA1 predispose carriers to a high incidence of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through critical roles in DNA repair, cell-cycle arrest, and transcriptional control. A major question has been why BRCA1 loss or mutation leads to tumors mainly in estrogen-regulated tissues, given that BRCA1 has essential functions in all cell types. Here, we report that estrogen and estrogen metabolites can cause DNA double-strand breaks (DSB) in estrogen receptor-α-negative breast cells and that BRCA1 is required to repair these DSBs to prevent metabolite-induced genomic instability. We found that BRCA1 also regulates estrogen metabolism and metabolite-mediated DNA damage by repressing the transcription of estrogen-metabolizing enzymes, such as CYP1A1, in breast cells. Finally, we used a knock-in human cell model with a heterozygous BRCA1 pathogenic mutation to show how BRCA1 haploinsufficiency affects these processes. Our findings provide pivotal new insights into why BRCA1 mutation drives the formation of tumors in estrogen-regulated tissues, despite the general role of BRCA1 in DNA repair in all cell types.

AB - Germline mutations in BRCA1 predispose carriers to a high incidence of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through critical roles in DNA repair, cell-cycle arrest, and transcriptional control. A major question has been why BRCA1 loss or mutation leads to tumors mainly in estrogen-regulated tissues, given that BRCA1 has essential functions in all cell types. Here, we report that estrogen and estrogen metabolites can cause DNA double-strand breaks (DSB) in estrogen receptor-α-negative breast cells and that BRCA1 is required to repair these DSBs to prevent metabolite-induced genomic instability. We found that BRCA1 also regulates estrogen metabolism and metabolite-mediated DNA damage by repressing the transcription of estrogen-metabolizing enzymes, such as CYP1A1, in breast cells. Finally, we used a knock-in human cell model with a heterozygous BRCA1 pathogenic mutation to show how BRCA1 haploinsufficiency affects these processes. Our findings provide pivotal new insights into why BRCA1 mutation drives the formation of tumors in estrogen-regulated tissues, despite the general role of BRCA1 in DNA repair in all cell types.

M3 - Article

VL - 74

SP - 2773

EP - 2784

JO - Cancer Research

T2 - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 10

ER -

Savage KI, Matchett KB, Barros EM, Cooper KM, Irwin GW, Gorski JJ et al. BRCA1 deficiency exacerbates estrogen-induced DNA damage and genomic instability. Cancer Research. 2014 May 15;74(10):2773-2784.