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

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 tria

SUBMITTER: Haricharan S 

PROVIDER: S-EPMC5733075 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature