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

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Invasive lobular carcinoma (ILC) of the breast, despite being estrogen receptor α (ER)-positive, exhibits poor patient outcomes and high recurrence rates.
• This suggests a unique ER function and endocrine response in ILC compared to other breast cancer subtypes.
• Estrogen receptor α (ER) activity in ILC is specifically co-regulated by the DNA repair protein MDC1.

Purpose of the Study:

• To investigate how MDC1 regulates ER activity and DNA repair in ILC by profiling the MDC1 interactome.
• To understand the molecular mechanisms underlying ILC's divergent endocrine response and high recurrence risk.

Main Methods:

• Profiling the MDC1 interactome in ILC cells.
• Performing single-cell transcriptome analysis and DNA repair activity assays.
• Analyzing DNA repair signaling and functional data in ILC tumors.
• In vitro and in vivo xenograft studies using the PARP inhibitor talazoparib.

Main Results:

• MDC1-associated proteins in ILC cells indicated a "BRCA-like" state with homologous recombination (HR) protein deficiency, signifying HR dysfunction distinct from classic "BRCAness".
• ILC cells demonstrated impaired HR induction and execution, with tumor data showing elevated signatures of PARP inhibitor sensitivity.
• Treatment with talazoparib resulted in significant and durable growth suppression of ILC both in vitro and in vivo.

Conclusions:

• ILC-specific ER:MDC1 activity is linked to DNA repair dysfunction.
• This DNA repair defect presents a potential therapeutic vulnerability in ILC.
• Targeting this dysfunction with PARP inhibitors like talazoparib shows promise for ILC treatment.