BRCA1 RING Function Is Essential for Tumor Suppression but Dispensable for Therapy Resistance

R Drost; P Bouwman; S Rottenberg; U Boon; E Schut; S Klarenbeek; C Klijn; I van der Heijden; H van der Gulden; E Wientjens; M Pieterse; A Catteau; P Green; E Solomon; Jo Morris; J Jonkers

doi:10.1016/j.ccr.2011.11.014

BRCA1 RING Function Is Essential for Tumor Suppression but Dispensable for Therapy Resistance

R Drost, P Bouwman, S Rottenberg, U Boon, E Schut, S Klarenbeek, C Klijn, I van der Heijden, H van der Gulden, E Wientjens, M Pieterse, A Catteau, P Green, E Solomon, Jo Morris, J Jonkers

Cancer and Genomic Sciences

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Abstract

Hereditary breast cancers are frequently caused by germline BRCA1 mutations. The BRCA1(C61G) mutation in the BRCA1 RING domain is a common pathogenic missense variant, which reduces BRCA1/BARD1 heterodimerization and abrogates its ubiquitin ligase activity. To investigate the role of BRCA1 RING function in tumor suppression and therapy response, we introduced the Brca1(C61G) mutation in a conditional mouse model for BRCA1-associated breast cancer. In contrast to BRCA1-deficient mammary carcinomas, tumors carrying the Brca1(C61G) mutation responded poorly to platinum drugs and PARP inhibition and rapidly developed resistance while retaining the Brca1(C61G) mutation. These findings point to hypomorphic activity of the BRCA1-C61G protein that, although unable to prevent tumor development, affects response to therapy.

Original language	English
Pages (from-to)	797-809
Number of pages	13
Journal	Cancer Cell
Volume	20
Issue number	6
DOIs	https://doi.org/10.1016/j.ccr.2011.11.014
Publication status	Published - 1 Dec 2011

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Drost, R., Bouwman, P., Rottenberg, S., Boon, U., Schut, E., Klarenbeek, S., Klijn, C., van der Heijden, I., van der Gulden, H., Wientjens, E., Pieterse, M., Catteau, A., Green, P., Solomon, E., Morris, J., & Jonkers, J. (2011). BRCA1 RING Function Is Essential for Tumor Suppression but Dispensable for Therapy Resistance. Cancer Cell, 20(6), 797-809. https://doi.org/10.1016/j.ccr.2011.11.014

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title = "BRCA1 RING Function Is Essential for Tumor Suppression but Dispensable for Therapy Resistance",

abstract = "Hereditary breast cancers are frequently caused by germline BRCA1 mutations. The BRCA1(C61G) mutation in the BRCA1 RING domain is a common pathogenic missense variant, which reduces BRCA1/BARD1 heterodimerization and abrogates its ubiquitin ligase activity. To investigate the role of BRCA1 RING function in tumor suppression and therapy response, we introduced the Brca1(C61G) mutation in a conditional mouse model for BRCA1-associated breast cancer. In contrast to BRCA1-deficient mammary carcinomas, tumors carrying the Brca1(C61G) mutation responded poorly to platinum drugs and PARP inhibition and rapidly developed resistance while retaining the Brca1(C61G) mutation. These findings point to hypomorphic activity of the BRCA1-C61G protein that, although unable to prevent tumor development, affects response to therapy.",

author = "R Drost and P Bouwman and S Rottenberg and U Boon and E Schut and S Klarenbeek and C Klijn and I van der Heijden and H van der Gulden and E Wientjens and M Pieterse and A Catteau and P Green and E Solomon and Jo Morris and J Jonkers",

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Drost, R, Bouwman, P, Rottenberg, S, Boon, U, Schut, E, Klarenbeek, S, Klijn, C, van der Heijden, I, van der Gulden, H, Wientjens, E, Pieterse, M, Catteau, A, Green, P, Solomon, E, Morris, J & Jonkers, J 2011, 'BRCA1 RING Function Is Essential for Tumor Suppression but Dispensable for Therapy Resistance', Cancer Cell, vol. 20, no. 6, pp. 797-809. https://doi.org/10.1016/j.ccr.2011.11.014

TY - JOUR

T1 - BRCA1 RING Function Is Essential for Tumor Suppression but Dispensable for Therapy Resistance

AU - Drost, R

AU - Bouwman, P

AU - Rottenberg, S

AU - Boon, U

AU - Schut, E

AU - Klarenbeek, S

AU - Klijn, C

AU - van der Heijden, I

AU - van der Gulden, H

AU - Wientjens, E

AU - Pieterse, M

AU - Catteau, A

AU - Green, P

AU - Solomon, E

AU - Morris, Jo

AU - Jonkers, J

PY - 2011/12/1

Y1 - 2011/12/1

N2 - Hereditary breast cancers are frequently caused by germline BRCA1 mutations. The BRCA1(C61G) mutation in the BRCA1 RING domain is a common pathogenic missense variant, which reduces BRCA1/BARD1 heterodimerization and abrogates its ubiquitin ligase activity. To investigate the role of BRCA1 RING function in tumor suppression and therapy response, we introduced the Brca1(C61G) mutation in a conditional mouse model for BRCA1-associated breast cancer. In contrast to BRCA1-deficient mammary carcinomas, tumors carrying the Brca1(C61G) mutation responded poorly to platinum drugs and PARP inhibition and rapidly developed resistance while retaining the Brca1(C61G) mutation. These findings point to hypomorphic activity of the BRCA1-C61G protein that, although unable to prevent tumor development, affects response to therapy.

AB - Hereditary breast cancers are frequently caused by germline BRCA1 mutations. The BRCA1(C61G) mutation in the BRCA1 RING domain is a common pathogenic missense variant, which reduces BRCA1/BARD1 heterodimerization and abrogates its ubiquitin ligase activity. To investigate the role of BRCA1 RING function in tumor suppression and therapy response, we introduced the Brca1(C61G) mutation in a conditional mouse model for BRCA1-associated breast cancer. In contrast to BRCA1-deficient mammary carcinomas, tumors carrying the Brca1(C61G) mutation responded poorly to platinum drugs and PARP inhibition and rapidly developed resistance while retaining the Brca1(C61G) mutation. These findings point to hypomorphic activity of the BRCA1-C61G protein that, although unable to prevent tumor development, affects response to therapy.

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DO - 10.1016/j.ccr.2011.11.014

M3 - Article

C2 - 22172724

VL - 20

SP - 797

EP - 809

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

BRCA1 RING Function Is Essential for Tumor Suppression but Dispensable for Therapy Resistance

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