TGFβ induces "BRCAness" and sensitivity to PARP inhibition in breast cancer by regulating DNA-repair genes.
TGFβ induces "BRCAness" and sensitivity to PARP inhibition in breast cancer by regulating DNA-repair genes.
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DOI：
10.1158/1541-7786.mcr-14-0201
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发表时间：
2014-11
期刊：
影响因子：
--
通讯作者：
Wang SE
中科院分区：
文献类型：
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作者：
Liu L;Zhou W;Cheng CT;Ren X;Somlo G;Fong MY;Chin AR;Li H;Yu Y;Xu Y;O'Connor ST;O'Connor TR;Ann DK;Stark JM;Wang SE
转化生长因子β（TGFβ）蛋白是一种多任务细胞因子，其在肿瘤部位的高水平通常与人类癌症患者的不良预后相关。以前有报道TGFβ通过miRNA介导的机制下调乳腺癌（BC）细胞中共济失调毛细血管扩张突变（ATM）和mutS同源物2（MSH 2）的表达。在这项研究中，检测了一组DNA修复基因的表达，将乳腺癌1，早发性（BRCA 1）确定为TGFβ通过miR-181家族下调的靶点。TGFβ1的表达水平与miR-181/BRCA 1轴在原发性乳腺肿瘤标本中的表达水平之间存在相关性。通过下调BRCA 1、ATM和MSH 2，TGFβ协调某些BC细胞中的DNA损伤反应（DDR）以诱导“BRCAness”表型，包括受损的DNA修复效率和对聚（ADP-核糖）聚合酶（PARP）抑制的合成致死性。具有活性TGFβ信号传导的异种移植肿瘤表现出对DNA损伤剂阿霉素的抗性，但对PARP抑制剂ABT-888的敏感性增加。阿霉素联合ABT-888显著改善了TGFβ活性肿瘤的治疗效果。因此，TGFβ可以在携带野生型BRCA基因的某些BC中诱导“BRCAness”，并增强对PARP抑制的反应性，并表征了其背后的分子机制。含义：这些发现使得能够更好地选择散发性乳腺癌患者进行PARP干预，这在携带BRCA突变的患者中表现出有益的效果。
Transforming growth factor β (TGFβ) proteins are multitasking cytokines, whose high levels at tumor sites generally correlate with poor prognosis in human cancer patients. Previously it was reported that TGFβ downregulates the expression of ataxia telangiectasia mutated (ATM) and mutS homolog 2 (MSH2) in breast cancer (BC) cells through a miRNA-mediated mechanism. In this study, expression of a panel of DNA repair genes was examined, identifying breast cancer 1, early onset (BRCA1) as a target downregulated by TGFβ through the miR-181 family. Correlations between the expression levels of TGFβ1 and the miR-181/BRCA1 axis were observed in primary breast tumor specimens. By downregulating BRCA1, ATM, and MSH2, TGFβ orchestrates DNA damage response (DDR) in certain BC cells to induce a ‘BRCAness’ phenotype, including impaired DNA repair efficiency and synthetic lethality to the inhibition of poly (ADP-ribose) polymerase (PARP). Xenograft tumors with active TGFβ signaling exhibited resistance to the DNA-damaging agent doxorubicin but increased sensitivity to the PARP inhibitor ABT-888. Combination of doxorubicin with ABT-888 significantly improved the treatment efficacy in TGFβ-active tumors. Thus, TGFβ can induce ‘BRCAness’ in certain BCs carrying wild-type BRCA genes and enhance the responsiveness to PARP inhibition, and the molecular mechanism behind this is characterized. Implications: These findings enable better selection of sporadic breast cancer patients for PARP interventions, which have exhibited beneficial effects in patients carrying BRCA mutations.