Co-regulator activity of Mediator of DNA Damage Checkpoint 1 (MDC1) is associated with DNA repair dysfunction and PARP inhibitor sensitivity in lobular carcinoma of the breast

Invasive lobular carcinoma of the breast (ILC) are typically estrogen receptor α (ER)-positive and present with biomarkers of anti-estrogen sensitive disease, yet patients with ILC face uniquely poor long-term outcomes with increased recurrence risk, suggesting endocrine response and ER function are unique in ILC. We previously found specifically in ILC cells that ER is co-regulated by the DNA repair protein Mediator of DNA Damage Checkpoint 1 (MDC1). This novel MDC1 activity, however, was associated with dysfunction in the canonical DNA repair activity of MDC1, but absent typical features of DNA repair deficiency. To understand reciprocal activities of MDC1, we profiled the MDC1 interactome and found MDC1-associated proteins in ILC cells mirror a "BRCA-like" state lacking key homologous recombination (HR) proteins, consistent with HR dysfunction but distinct from classic "BRCAness". HR dysfunction in ILC cells was mirrored in single-cell transcriptome and DNA repair activity analyses, along with DNA repair signaling and functional data, showing dysfunctional HR induction and resolution. In parallel, ILC tumor data are consistent with a distinct form of HR dysfunction via impaired HR resolution, lacking BRCA-like genomic scarring but with elevated signatures of PARP inhibitor sensitivity. We tested whether this HR dysfunction could indeed be exploited using PARP inhibition and found that talazoparib treatment produced a durable growth suppression in vitro and in multiple ILC xenografts in vivo. ILC-specific ER:MDC1 activity creates a new context for ER and MDC1 function in ILC, at the cost of a DNA repair dysfunction that is therapeutically targetable.