Department of Medicine, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University, Nashville, Tennessee, USA.
Nat Med. 2012 Jul;18(7):1052-9. doi: 10.1038/nm.2795.
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.
新辅助化疗（NAC）可使约 30%的乳腺癌患者病理完全缓解（pCR）。然而，许多患者在化疗后仍有残留肿瘤，与 pCR 患者相比，这些患者具有更高的转移复发风险和更差的预后。我们假设 NAC 后肿瘤的分子谱分析将鉴定与耐药相关的基因。数字转录计数用于分析 NAC 后手术切除的乳腺癌。双特异性蛋白磷酸酶 4（DUSP4）的低浓度，一种 ERK 磷酸酶，与高 post-NAC 肿瘤细胞增殖和基底样乳腺癌（BLBC）状态相关。BLBC 具有更高的 DUSP4 启动子甲基化和 Ras-ERK 通路激活的基因表达模式，相对于其他乳腺癌亚型。DUSP4 的过表达增加了化疗诱导的细胞凋亡，而 DUSP4 的耗竭则抑制了对化疗的反应。NAC 后原发肿瘤中 DUSP4 表达的降低与治疗耐药性高 Ki-67 评分和较短的无复发生存相关。最后，丝裂原活化蛋白激酶激酶（MEK）抑制剂与 BLBC 异种移植中的多西紫杉醇协同作用。因此，DUSP4 的下调激活了 BLBC 中的 Ras-ERK 通路，导致对抗癌化疗的反应减弱。
