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 alpha (ER)-positive and present with biomarkers of anti-estrogen sensitive disease, but growing laboratory and clinical data, including poor long-term outcomes faced by patients with ILC, suggest endocrine response and ER function are unique in ILC. We previously identified the DNA repair protein Mediator of DNA Damage Checkpoint 1 (MDC1) as an ILC-specific ER co-regulator necessary for ER genomic activity, and that MDC1 co-regulator activity was associated with dysfunctional canonical DNA repair roles of MDC1. To understand these potentially reciprocal activities of MDC1 in ILC, we profiled the MDC1 interactome and found that MDC1 associated proteins in ILC cells mirror a BRCA-mutant-like state lacking MDC1 interaction with key homologous recombination (HR) proteins. Single-cell gene expression and DNA repair activity showed that specific activation of ER:MDC1 target genes was associated with increased PARP-associated DNA repair and decreased HR gene expression. These data suggest that HR is dysfunctional in ILC, which was supported by a lack of DNA damage-induced RAD51 turnover in ILC cells, and an elevated DNA damage response protein signature in a subset of ILC tumors. We tested whether this HR dysfunction could be exploited using PARP inhibition, and found that talazoparib treatment produced a durable growth suppression both in vitro and in ILC cell line xenografts in vivo. The ILC-specific ER:MDC1 association creates a new context for ER and MDC1 function in ILC, at the cost of a DNA repair dysfunction that may be therapeutically targetable. Significance: ILC are rarely associated with biomarkers of overt HR deficiency, as such patients are rarely eligible for treatment with PARP inhibitors. Our work suggests ILC present with a previously unappreciated form of HR dysfunction, linked to ILC-specific genomic activity of ER, that imparts sensitivity to PARP inhibition. ### Competing Interest Statement The authors have declared no competing interest.