SIX1 Oncoprotein as a Biomarker in a Model of Hormonal Carcinogenesis and in Human Endometrial Cancer.
SIX1 Oncoprotein as a Biomarker in a Model of Hormonal Carcinogenesis and in Human Endometrial Cancer.
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DOI：
10.1158/1541-7786.mcr-16-0084
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发表时间：
2016-09
期刊：
影响因子：
--
通讯作者：
Williams CJ
中科院分区：
文献类型：
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作者：
Suen AA;Jefferson WN;Wood CE;Padilla-Banks E;Bae-Jump VL;Williams CJ
癌胚蛋白sine oculis-related homeobox 1（SIX 1）是一种与多种人类癌症类型的癌变相关的发育转录因子，但尚未在人类子宫内膜癌中进行研究。在一个激素致癌模型中，雌性小鼠暴露于大豆植物雌激素染料木黄酮（GEN）或合成雌激素己烯雌酚（DES），成年后会患子宫内膜癌。先前，我们证明SIX 1在这些小鼠的子宫中异常表达。在这里，我们使用这种小鼠模型来研究SIX 1表达在子宫内膜癌发展中的作用，并使用人类组织微阵列来探索SIX 1作为人类子宫内膜癌生物标志物的实用性。在子宫内暴露于GEN或DES的小鼠中，Six 1转录水平在6、12和18个月大的子宫内随时间显著增加，并与子宫内膜癌的发生相关。SIX 1蛋白定位于异常基底细胞和所有非典型增生和肿瘤性病变。这些研究结果表明，发育雌激素化学品暴露诱导持续子宫内膜SIX 1的表达，这是强烈相关的异常细胞分化和癌症的发展。在人类子宫内膜组织标本中，SIX 1在正常子宫内膜中不存在，但在更有可能患有晚期疾病的子宫内膜癌患者中表达。这些发现将SIX 1确定为激素致癌模型中的疾病生物标志物，并表明SIX 1在小鼠和女性的子宫内膜癌发展中起作用。SIX 1癌蛋白在发育期暴露于雌激素化学物质后在子宫中异常表达，与子宫癌相关，并且是人类子宫内膜癌的生物标志物。
The oncofetal protein sine oculis-related homeobox 1 (SIX1) is a developmental transcription factor associated with carcinogenesis in several human cancer types, but has not been investigated in human endometrial cancer. In a model of hormonal carcinogenesis, mice neonatally exposed to the soy phytoestrogen genistein (GEN) or the synthetic estrogen diethylstilbestrol (DES) develop endometrial cancer as adults. Previously, we demonstrated that SIX1 becomes aberrantly expressed in the uteri of these mice. Here we used this mouse model to investigate the role of SIX1 expression in endometrial carcinoma development and used human tissue microarrays to explore the utility of SIX1 as a biomarker in human endometrial cancer. In mice neonatally exposed to GEN or DES, the Six1 transcript level increased dramatically over time in uteri at 6, 12, and 18 months of age and was associated with development of endometrial carcinoma. SIX1 protein localized within abnormal basal cells and all atypical hyperplastic and neoplastic lesions. These findings indicate that developmental estrogenic chemical exposure induces persistent endometrial SIX1 expression that is strongly associated with abnormal cell differentiation and cancer development. In human endometrial tissue specimens, SIX1 was not present in normal endometrium but was expressed in a subset of endometrial cancers in patients who were also more likely to have late-stage disease. These findings identify SIX1 as a disease biomarker in a model of hormonal carcinogenesis and suggest that SIX1 plays a role in endometrial cancer development in both mice and women. The SIX1 oncoprotein is aberrantly expressed in the uterus following developmental exposure to estrogenic chemicals, correlates with uterine cancer, and is a biomarker in human endometrial cancers.