近日,，一項由Vanderbilt-Ingram癌癥中心（VICC）研究人員領(lǐng)導(dǎo)的研究發(fā)現(xiàn)或許可以解釋為什么化療對某些腫瘤的治療效果比手術(shù)低,，并描繪了具體亞型乳腺癌患者的基因表達模式,，研究結(jié)果發(fā)表在Nature Medicine雜志上,。
在先使用化療進行治療時,，約30％的乳腺癌患者有反應(yīng),。然而在新輔助化療（NAC）進行完后,，仍然有許多患者有乳房癌殘留。這些患者癌癥復(fù)發(fā)和死亡的風險較高,。
研究人員人員分析新輔助化療后殘留腫瘤細胞抵抗這種治療形式的相關(guān)基因,。他們研究了49例手術(shù)4個月后的乳腺腫瘤患者NAC基因表達模式。
他們發(fā)現(xiàn)了與化療耐藥腫瘤相關(guān)的特定基因群體,，研究者發(fā)現(xiàn)低濃度的雙特異性蛋白磷酸酶4（DUSP4）與接受新輔助化療后腫瘤細胞的快速生長相關(guān),。低DUSP4與基底樣乳腺癌（BLBC）生長相關(guān)。DUSP4啟動子甲基化和基因表達模式的Ras-ERK通路的激活也較高,。
當DUSP4存在時,，化療對癌細胞有效，而去除DUSP4時,，化療反應(yīng)的治療效果降低,。這些數(shù)據(jù)表明低DUSP4表達是耐藥性和腫瘤復(fù)發(fā)的一個潛在生物標志物。（生物谷：Bioon.com）
doi:10.1038/nm.2795
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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.
