For patients carrying BRCA1 mutations, at least one-third develop triple negative breast cancer (TNBC). Not only is TNBC difficult to treat due to the lack of molecular target receptors, but BRCA1 mutations (BRCA1m) also result in chemotherapeutic resistance, making disease recurrence more likely. Although BRCA1m are highly heterogeneous and therefore difficult to target, BRCA1 gene's synthetic lethal pair, PARP1, is conserved in BRCA1m cancer cells. Therefore, we hypothesize that targeting PARP1 might be a fruitful direction to sensitize BRCA1m cancer cells to chemotherapy. We used CRISPR/Cas9 technology to generate PARP1 deficiency in two TNBC cell lines, MDA-MB-231 (BRCA1 wild-type) and MDA-MB-436 (BRCA1m). We explored whether this PARP1 disruption (PARP1m) could significantly lower the chemotherapeutic dose necessary to achieve therapeutic efficacy in both a 2D and 3D tumor-on-a-chip model. With both BRCA1m and PARP1m, the TNBC cells were more sensitive to three representative chemotherapeutic breast cancer drugs, doxorubicin, gemcitabine and docetaxel, compared with the PARP1 wild-type counterpart in the 2D culture environment. However, PARP1m did not result in this synergy in the 3D tumor-on-a-chip model, suggesting that drug dosing in the tumor microenvironment may influence the synergy. Taken together, our results highlight a discrepancy in the efficacy of the combination of PARP1 inhibition and chemotherapy for TNBC treatment, which should be clarified to justify further clinical testing.

中文翻译：

---

CRISPR/Cas9 介导的诱变，以验证 PARP1 抑制和化疗在 BRCA1 突变乳腺癌细胞中的协同作用。


对于携带 BRCA1 突变的患者，至少三分之一会发展为三阴性乳腺癌 (TNBC)。 TNBC不仅因缺乏分子靶受体而难以治疗，而且BRCA1突变（BRCA1m）还会导致化疗耐药，使疾病复发的可能性更大。尽管 BRCA1m 具有高度异质性，因此难以靶向，但 BRCA1 基因的合成致死对 PARP1 在 BRCA1m 癌细胞中是保守的。因此，我们假设靶向 PARP1 可能是使 BRCA1m 癌细胞对化疗敏感的有效方向。我们使用 CRISPR/Cas9 技术在两种 TNBC 细胞系 MDA-MB-231（BRCA1 野生型）和 MDA-MB-436（BRCA1m）中产生 PARP1 缺陷。我们探讨了这种 PARP1 破坏 (PARP1m) 是否可以显着降低在 2D 和 3D 芯片肿瘤模型中实现治疗效果所需的化疗剂量。与 2D 培养环境中的 PARP1 野生型对应物相比，具有 BRCA1m 和 PARP1m 的 TNBC 细胞对三种代表性化疗乳腺癌药物阿霉素、吉西他滨和多西他赛更敏感。然而，PARP1m 在 3D 芯片肿瘤模型中并未产生这种协同作用，这表明肿瘤微环境中的药物剂量可能会影响协同作用。总而言之，我们的结果强调了 PARP1 抑制和化疗联合治疗 TNBC 的疗效存在差异，应该澄清这一点，以证明进一步临床测试的合理性。