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Cancer Discov. 2017 Oct;7(10):1168-1183. doi: 10.1158/2159-8290.CD-16-1179. Epub 2017 Aug 11.

Loss of MutL Disrupts CHK2-Dependent Cell-Cycle Control through CDK4/6 to Promote Intrinsic Endocrine Therapy Resistance in Primary Breast Cancer.

Author information

1
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
2
Department of Medicine, Baylor College of Medicine, Houston, Texas.
3
Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas.
4
Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota.
5
Department of Breast Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
6
Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland.
7
Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri.
8
Siteman Cancer Center Breast Cancer Program, Washington University School of Medicine, Saint Louis, Missouri.
9
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
10
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
11
Department of Immunology and Pathology, Baylor College of Medicine, Houston, Texas.
12
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
13
Rady's Children's Hospital, San Diego, California.
14
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. mjellis@bcm.edu.

Abstract

Significant endocrine therapy-resistant tumor proliferation is present in ≥20% of estrogen receptor-positive (ER+) primary breast cancers and is associated with disease recurrence and death. Here, we uncover a link between intrinsic endocrine therapy resistance and dysregulation of the MutL mismatch repair (MMR) complex (MLH1/3, PMS1/2), and demonstrate a direct role for MutL complex loss in resistance to all classes of endocrine therapy. We find that MutL deficiency in ER+ breast cancer abrogates CHK2-mediated inhibition of CDK4, a prerequisite for endocrine therapy responsiveness. Consequently, CDK4/6 inhibitors (CDK4/6i) remain effective in MutL-defective ER+ breast cancer cells. These observations are supported by data from a clinical trial where a CDK4/6i was found to strongly inhibit aromatase inhibitor-resistant proliferation of MutL-defective tumors. These data suggest that diagnostic markers of MutL deficiency could be used to direct adjuvant CDK4/6i to a population of patients with breast cancer who exhibit marked resistance to the current standard of care.Significance: MutL deficiency in a subset of ER+ primary tumors explains why CDK4/6 inhibition is effective against some de novo endocrine therapy-resistant tumors. Therefore, markers of MutL dysregulation could guide CDK4/6 inhibitor use in the adjuvant setting, where the risk benefit ratio for untargeted therapeutic intervention is narrow. Cancer Discov; 7(10); 1168-83. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1047.

PMID:
28801307
PMCID:
PMC5733075
DOI:
10.1158/2159-8290.CD-16-1179
[Indexed for MEDLINE]
Free PMC Article

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