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

ABSTRACT: Invasive lobular carcinoma of the breast (ILC) is typically estrogen receptor α (ER)-positive and presents with biomarkers of anti-estrogen 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 to other breast cancers. ER is co-regulated by the DNA repair protein MDC1 specifically in ILC cells, driving distinct ER activity. Here, 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE312599 | GEO | 2025/12/17

REPOSITORIES: GEO

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Project description:Purpose:Triple negative breast cancer (TNBC) commonly metastasizes to the brain and predicts poor prognosis with limited therapeutic options. TNBC frequently harbors BRCA mutations translating to platinum sensitivity; platinum response may be augmented by additional suppression of DNA repair mechanisms through poly(ADP-ribose)polymerase (PARP) inhibition. We evaluated brain penetrance and efficacy of Carboplatin +/- the PARP inhibitor ABT888, and investigated gene expression changes in murine intracranial (IC) TNBC models stratified by BRCA and molecular subtype status. Experimental design:Athymic mice were inoculated intra-cerebrally with BRCA-mutant: SUM149 (basal), MDA-MB-436 (claudin-low), or BRCA-wild-type: MDA-MB-468 (basal), MDA-MB-231BR (claudin-low) TNBC cells and treated with PBS control (IP, weekly), Carboplatin (50mg/kg/week, IP), ABT888 (25mg/kg/day, OG), or their combination. DNA-damage (?-H2AX) and apoptosis (cleaved-Caspase-3(cC3)) were assessed via IHC of IC tumors. Gene expression of BRCA-mutant IC tumors was measured. Results: Carboplatin+/-ABT888 significantly improved survival in BRCA-mutant IC models compared to control, but did not improve survival in BRCA-wild-type IC models. Carboplatin+ABT888 revealed a modest survival advantage versus Carboplatin in BRCA-mutant models. ABT888 yielded a marginal survival benefit in the MDA-MB-436 but not in the SUM149 model. BRCA-mutant SUM149 expression of ?-H2AX and cC3 proteins was elevated in all treatment groups compared to Control, while BRCA-wild-type MDA-MB-468 cC3 expression did not increase with treatment. Carboplatin treatment induced common gene expression changes in BRCA-mutant models.Conclusions: Carboplatin+/-ABT888 improves survival in BRCA-mutant IC TNBC models with corresponding DNA damage and gene expression changes. Combination therapy represents a promising treatment strategy for patients with TNBC brain metastases warranting further clinical investigation. reference x sample

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

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