Altered MDC1 Interactions and Dysfunctional DNA Repair in Lobular Breast Cancer Confers Sensitivity to PARP Inhibition.

Invasive lobular carcinoma of the breast (ILC) is typically estrogen receptor α (ER)-positive and presents with biomarkers of antiestrogen sensitive disease. Unfortunately, patients with ILC face particularly poor long-term outcomes with high recurrence risk, suggesting a divergent endocrine response and ER function in ILC compared with other breast cancers. ER is coregulated by the DNA repair protein mediator of DNA damage checkpoint 1 (MDC1), specifically in ILC cells, driving distinct ER activity. In this study, we profiled the MDC1 interactome to examine how MDC1 regulates ER activity and DNA repair function in ILC. MDC1-associated proteins in ILC cells mirrored a "BRCA-like" state lacking key homologous recombination (HR) proteins, consistent with HR dysfunction but distinct from classic "BRCAness." Single-cell transcriptome and DNA repair activity analyses, along with DNA repair signaling and functional data, substantiated dysfunctional induction and execution of HR in ILC cells. In parallel, ILC tumor data were consistent with a form of HR dysfunction distinct from overt HR deficiency, lacking BRCA-like genomic scarring but showing elevated signatures of PARP inhibitor sensitivity. Treatment with the PARP inhibitor talazoparib produced a durable growth suppression both in vitro and in multiple ILC xenografts in vivo. Together, these findings reveal that ILC-specific ER:MDC1 activity comes at the cost of DNA repair dysfunction, which may be therapeutically targetable. SIGNIFICANCE: Association between ER and MDC1 in lobular breast cancer cells induces a form of dysfunctional homologous recombination, distinct from "BRCAness," that creates the mechanistic context for synthetic lethal interaction with PARP inhibition.