Amplification of LAPTM4B and YWHAZ contributes to chemotherapy resistance and recurrence of breast cancer.
Amplification of LAPTM4B and YWHAZ contributes to chemotherapy resistance and recurrence of breast cancer.
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DOI：
10.1038/nm.2090
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发表时间：
2010-02
期刊：
影响因子：
82.9
通讯作者：
Wang, Zhigang Charles
中科院分区：
文献类型：
--
作者：
Li, Yang;Zou, Lihua;Li, Qiyuan;Haibe-Kains, Benjamin;Tian, Ruiyang;Li, Yan;Desmedt, Christine;Sotiriou, Christos;Szallasi, Zoltan;Iglehart, J. Dirk;Richardson, Andrea L.;Wang, Zhigang Charles
乳腺癌术后辅助化疗有效地降低了转移复发率。然而，尽管辅助性治疗，仍有相当比例的女性在远处转移部位复发癌症。识别对特定化疗药物的肿瘤反应至关重要的基因是一项挑战，但对于改善结果是必要的。利用整合基因组学，我们发现了染色体8q22上少量过度表达和扩增的基因，这些基因与早期疾病复发显著相关，尽管使用的是基于蒽环类药物的辅助化疗。在对多个独立队列的分析中，这种相关性得到了证实。其中两个基因，抗凋亡基因YWHAZ和新的溶酶体基因LAPTM4B，当两个基因中的任何一个被siRNA敲除时，会使肿瘤细胞对蒽环类药物敏感，当其中一个基因过度表达时，会诱导肿瘤细胞产生耐药性。LAPTM4B过表达导致药物滞留，延迟其在细胞核内的出现。在一项新辅助化疗试验中，在女性乳腺癌患者中，这两个基因的过度表达与肿瘤对蒽环类药物治疗的不良反应有关。我们的结果表明，8q22扩增和LAPTM4B和YWHAZ的过度表达导致了对蒽环类药物的从头化疗耐药，并允许转移复发。这两个基因可能预测对蒽环类药物的耐药性，并影响化疗的选择。
Post-surgery adjuvant chemotherapy for breast cancer has effectively reduced metastatic recurrence rates. However, a significant proportion of women suffer recurrent cancer at distant metastatic sites despite adjuvant treatment. Identification of the genes critical for tumor response to specific chemotherapy drugs is a challenge, but necessary to improve outcomes. Using integrated genomics, we identified a small number of over-expressed and amplified genes from chromosome 8q22 significantly associated with early disease recurrence despite anthracycline-based adjuvant chemotherapy. The association was confirmed in an analysis of multiple independent cohorts. Two of these genes, the anti-apoptotic gene YWHAZ, and LAPTM4B, a novel lysosomal gene, sensitized tumor cells to anthracyclines when either was depleted by siRNA knockdown and induced drug resistance when either was over-expressed. Over-expression of LAPTM4B resulted in sequestration of drug, delaying its appearance in the nucleus. Over-expression of these two genes was associated with poor tumor response to anthracycline treatment in a neo-adjuvant chemotherapy trial in women with primary breast cancer. Our results suggest that 8q22 amplification and over-expression of LAPTM4B and YWHAZ contribute to de novo chemoresistance to anthracyclines, and are permissive for metastatic recurrence. These two genes may predict anthracycline resistance and influence selection of chemotherapy.
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影响因子：
50.3
作者：
Hu G;Chong RA;Yang Q;Wei Y;Blanco MA;Li F;Reiss M;Au JL;Haffty BG;Kang Y
通讯作者：
Kang Y
影响因子：
8
作者：
Györffy, B;Serra, V;Schäfer, R
通讯作者：
Schäfer, R
影响因子：
4.8
作者：
Hogue, DL;Kerby, L;Ling, V
通讯作者：
Ling, V
影响因子：
3.8
作者：
Albertson, DG
通讯作者：
Albertson, DG
影响因子：
2
作者：
Pencina, MJ;D'Agostino, RB
通讯作者：
D'Agostino, RB