Nat Med：乳腺癌化疗耐药基因DUSP4被发现

近日，一项由Vanderbilt-Ingram癌症中心（VICC）研究人员领导的研究发现或许可以解释为什么化疗对某些肿瘤的治疗效果比手术低，并描绘了具体亚型乳腺癌患者的基因表达模式，研究结果发表在Nature Medicine杂志上。

在先使用化疗进行治疗时，约30％的乳腺癌患者有反应。然而在新辅助化疗（NAC）进行完后，仍然有许多患者有乳房癌残留。这些患者癌症复发和死亡的风险较高。

研究人员人员分析新辅助化疗后残留肿瘤细胞抵抗这种治疗形式的相关基因。他们研究了49例手术4个月后的乳腺肿瘤患者NAC基因表达模式。

他们发现了与化疗耐药肿瘤相关的特定基因群体，研究者发现低浓度的双特异性蛋白磷酸酶4（DUSP4）与接受新辅助化疗后肿瘤细胞的快速生长相关。低DUSP4与基底样乳腺癌（BLBC）生长相关。DUSP4启动子甲基化和基因表达模式的Ras-ERK通路的激活也较高。

当DUSP4存在时，化疗对癌细胞有效，而去除DUSP4时，化疗反应的治疗效果降低。这些数据表明低DUSP4表达是耐药性和肿瘤复发的一个潜在生物标志物。）

doi:10.1038/nm.2795
PMC:
PMID:

Profiling of residual breast cancers after neoadjuvant chemotherapy identifies DUSP4 deficiency as a mechanism of drug resistance

Justin M Balko,Rebecca S Cook,David B Vaught,María G Kuba,Todd W Miller,Neil E Bhola,Melinda E Sanders,Nara M Granja-Ingram,et al.

Neoadjuvant chemotherapy (NAC) induces a pathological complete response (pCR) in ~30% of patients with breast cancer. However, many patients have residual cancer after chemotherapy, which correlates with a higher risk of metastatic recurrence and poorer outcome than those who achieve a pCR. We hypothesized that molecular profiling of tumors after NAC would identify genes associated with drug resistance. Digital transcript counting was used to profile surgically resected breast cancers after NAC. Low concentrations of dual specificity protein phosphatase 4 (DUSP4), an ERK phosphatase, correlated with high post-NAC tumor cell proliferation and with basal-like breast cancer (BLBC) status. BLBC had higher DUSP4 promoter methylation and gene expression patterns of Ras-ERK pathway activation relative to other breast cancer subtypes. DUSP4 overexpression increased chemotherapy-induced apoptosis, whereas DUSP4 depletion dampened the response to chemotherapy. Reduced DUSP4 expression in primary tumors after NAC was associated with treatment-refractory high Ki-67 scores and shorter recurrence-free survival. Finally, inhibition of mitogen-activated protein kinase kinase (MEK) synergized with docetaxel treatment in BLBC xenografts. Thus, DUSP4 downregulation activates the Ras-ERK pathway in BLBC, resulting in an attenuated response to anti-cancer chemotherapy.