Combined genomic and phenotype screening reveals secretory factor SPINK1 as an invasion and survival factor associated with patient prognosis in breast cancer.
Combined genomic and phenotype screening reveals secretory factor SPINK1 as an invasion and survival factor associated with patient prognosis in breast cancer.
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DOI：
10.1002/emmm.201100150
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发表时间：
2011-08
影响因子：
11.1
通讯作者：
Liu, Edison T.
中科院分区：
文献类型：
--
作者：
Soon, Wendy WeiJia;Miller, Lance David;Black, Michael A.;Dalmasso, Cyril;Chan, Xiu Bin;Pang, Brendan;Ong, Chee Wee;Salto-Tellez, Manuel;Desai, Kartiki V.;Liu, Edison T.
驱动癌症进展的分泌因子是有吸引力的免疫治疗靶点。我们对多个乳腺肿瘤队列使用全基因组数据挖掘方法，对临床结果进行注释，以发现这些因素。我们发现丝氨酸蛋白酶抑制剂 Kazal 1 型 (SPINK1) 与雌激素受体阳性 (ER+) 病例的生存率较低有关。免疫组织化学显示，SPINK1 在正常乳腺中不存在，但存在于早期和晚期肿瘤中，其表达与 ER+ 肿瘤的较差生存率相关。在 ER− 病例中，预后效果未达到统计学显着性。强制表达和/或暴露于重组 SPINK1 可诱导侵袭性而不影响细胞增殖。然而，SPINK1 的下调导致细胞死亡。此外，由于 caspase-3 水平降低以及 Bcl2 和磷酸化 Bcl2 蛋白高表达，SPINK1 过表达细胞对药物诱导的细胞凋亡具有抵抗力。有趣的是，SPINK1 的这些抗凋亡作用被其蛋白酶抑制域的突变所消除。因此，SPINK1 影响乳腺癌的多种侵袭特性：生存、侵袭性和化疗耐药性。由于 SPINK1 的作用可被中和抗体消除，因此我们认为 SPINK1 是乳腺癌的可行的潜在治疗靶点。
Secretory factors that drive cancer progression are attractive immunotherapeutic targets. We used a whole-genome data-mining approach on multiple cohorts of breast tumours annotated for clinical outcomes to discover such factors. We identified Serine protease inhibitor Kazal-type 1 (SPINK1) to be associated with poor survival in estrogen receptor-positive (ER+) cases. Immunohistochemistry showed that SPINK1 was absent in normal breast, present in early and advanced tumours, and its expression correlated with poor survival in ER+ tumours. In ER− cases, the prognostic effect did not reach statistical significance. Forced expression and/or exposure to recombinant SPINK1 induced invasiveness without affecting cell proliferation. However, down-regulation of SPINK1 resulted in cell death. Further, SPINK1 overexpressing cells were resistant to drug-induced apoptosis due to reduced caspase-3 levels and high expression of Bcl2 and phospho-Bcl2 proteins. Intriguingly, these anti-apoptotic effects of SPINK1 were abrogated by mutations of its protease inhibition domain. Thus, SPINK1 affects multiple aggressive properties in breast cancer: survival, invasiveness and chemoresistance. Because SPINK1 effects are abrogated by neutralizing antibodies, we suggest that SPINK1 is a viable potential therapeutic target in breast cancer.
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影响因子：
17.1
作者：
Ateeq B;Tomlins SA;Laxman B;Asangani IA;Cao Q;Cao X;Li Y;Wang X;Feng FY;Pienta KJ;Varambally S;Chinnaiyan AM
通讯作者：
Chinnaiyan AM
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
50.3
作者：
Chin, Koei;DeVries, Sandy;Gray, Joe W.
通讯作者：
Gray, Joe W.
影响因子：
4.4
作者：
Hu, Zhiyuan;Fan, Cheng;Perou, Charles M.
通讯作者：
Perou, Charles M.
影响因子：
7.2
作者：
Lu, Xuanyong;Lamontagne, Jason;Block, Timothy M.
通讯作者：
Block, Timothy M.