揭示PGRMC1-PARP相互作用：三阴性乳腺癌中一种新型联合治疗策略

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by altered DNA repair pathway with insufficient therapeutic options. Poly (ADP-ribose) polymerase (PARP) is a key enzyme involved in DNA repair, and has emerged as an effective treatment for TNBC and BRCA-associated cancers in clinical trials. Despite these advances, 40-70% of patients ultimately develop resistance to PARPi, highlighting the need to identify additional modulators of therapeutic response. Previous work from our laboratory has shown that Progesterone Receptor Membrane Component 1 (PGRMC1) plays a critical role in regulating cancer cell growth by modulating PI3K/AKT/mTOR and EGFR signaling pathways in both ER-positive and TNBC cells. However, the mechanisms driving PGRMC1 overexpression in TNBC and its potential role in influencing PARP function remains unexplored. To address this challenge, we investigated the unexplored interaction between PARP inhibition and PGRMC1 inhibition in TNBC models. Methods: TNBC cell lines (BRCA-wild type: MDA-MB-231, MDA-MB-468; BRCA-mutant: HCC1395, MDA-MB-436) were treated with chemical inhibitors targeting PGRMC1 and PARP. Basal expression levels of PARP and PGRMC1 were compared between normal breast cells and TNBC cells by western blotting, and treatment-induced changes were quantified using western blot and qRT-PCR. Cell viability was measured by MTS assay and colony formation assay following inhibitor treatment across TNBC models. DNA damage was evaluated by gamma-H2AX and RAD51 immunofluorescence staining. Ferroptosis induction was assessed through intracellular iron quantification and flow cytometry. Results: We observed markedly elevated PGRMC1 expression in both BRCA-wild-type and BRCA-mutant TNBC cell lines compared with normal controls. Chemical inhibition of PGRMC1 or PARP led to increased DNA damage, evidenced by enhanced gamma-H2AX staining and reduced RAD51 levels. Modulating PGRMC1 significantly altered PARP expression, and reciprocal regulation was also observed. These treatments further induced DNA damage markers (gamma-H2AX, phospho-RAD51) and altered intracellular heme levels, promoting ferroptosis. The combination strategy effectively reduced cell survival regardless of BRCA mutation status, highlighting a strong dependence on PGRMC1 for survival under PARP inhibitor treatment. Conclusion: Targeting PGRMC1 may enhance PARPi response in TNBCs. This work identifies PGRMC1 as a promising therapeutic target and supports combination strategies for improving TNBC treatment. Future studies will dissect the mechanistic crosstalk between PGRMC1 and PARP using PGRMC1 knockdown and overexpression models.