Profiling of residual breast cancers after neoadjuvant chemotherapy identifies DUSP4 deficiency as a mechanism of drug resistance.
Profiling of residual breast cancers after neoadjuvant chemotherapy identifies DUSP4 deficiency as a mechanism of drug resistance.
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新辅助化疗（NAC）在约30%的乳腺癌患者中诱导出病理完全缓解（pCR）。然而，许多患者在化疗后仍有残留癌症，与达到pCR的患者相比，其转移复发风险更高且预后更差。我们假设对NAC后肿瘤进行分子分析将识别出与耐药相关的基因。采用数字转录计数对NAC后手术切除的乳腺癌进行分析。双特异性蛋白磷酸酶4（DUSP4，一种ERK磷酸酶）浓度低与NAC后肿瘤细胞高增殖以及基底样乳腺癌（BLBC）状态相关。与其他乳腺癌亚型相比，BLBC具有更高的DUSP4启动子甲基化以及Ras - ERK通路激活的基因表达模式。DUSP4过表达增加化疗诱导的细胞凋亡，而DUSP4缺失减弱对化疗的反应。NAC后原发性肿瘤中DUSP4表达降低与治疗难治性高Ki - 67评分以及更短的无复发生存期相关。最后，在BLBC异种移植物中，丝裂原活化蛋白激酶激酶（MEK）抑制剂与多西他赛治疗具有协同作用。因此，DUSP4下调激活BLBC中的Ras - ERK通路，导致对抗癌化疗的反应减弱。
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.
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影响因子：
3.8
作者：
Korde LA;Lusa L;McShane L;Lebowitz PF;Lukes L;Camphausen K;Parker JS;Swain SM;Hunter K;Zujewski JA
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