F344/NTac Rats Chronically Exposed to Bromodichloroacetic Acid Develop Mammary Adenocarcinomas With Mixed Luminal/Basal Phenotype and Tgfβ Dysregulation
F344/NTac Rats Chronically Exposed to Bromodichloroacetic Acid Develop Mammary Adenocarcinomas With Mixed Luminal/Basal Phenotype and Tgfβ Dysregulation
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DOI：
10.1177/0300985815571680
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发表时间：
2016-01-01
影响因子：
2.4
通讯作者：
Hoenerhoff, M. J.
中科院分区：
文献类型：
--
作者：
Harvey, J. B.;Hong, H. -H. L.;Hoenerhoff, M. J.
乳腺癌是最常见的癌症，也是美国女性癌症死亡的第二大原因。最近的一项为期2年的国家毒理学计划致癌性研究显示，暴露于溴二氯乙酸（BDCA）的F344/NTac大鼠中增生性乳腺病变（增生、纤维腺瘤、腺癌）的发生率增加，BDCA是一种人类广泛接触的成品饮用水中的消毒副产物。我们假设在BDCA暴露的F344/NTac大鼠中观察到的乳腺肿瘤增加可能是由于与人类乳腺癌相关的潜在分子变化。本研究的目的是比较正常未处理乳腺和对照动物与BDCA暴露动物乳腺肿瘤之间相关人类乳腺癌基因的（1）基因和蛋白质表达和（2）突变谱，以确定与人类癌症相关的分子变化。在组织学上，对照组和BDCA暴露组动物的腺癌在形态学上非常相似，雌激素/孕激素受体阳性，并显示混合腔/基底表型。基因表达分析显示，与人类乳腺癌相关的基因数量呈阳性趋势，BDCA治疗肿瘤组中的基因比例更高。此外，在BDCA处理的腺癌中观察到代表可能的Tgf β途径激活的5-基因签名，表明该途径可能与BDCA暴露动物中乳腺肿瘤发病率增加有关。
Breast cancer is the most common cancer and the second-leading cause of cancer mortality in women in the United States. A recent 2-year National Toxicology Program carcinogenicity study showed an increased incidence of proliferative mammary lesions (hyperplasia, fibroadenoma, adenocarcinoma) in F344/NTac rats exposed to bromodichloroacetic acid (BDCA), a disinfection by-product in finished drinking water with widespread human exposure. We hypothesized that the increase in mammary tumors observed in BDCA-exposed F344/NTac rats may be due to underlying molecular changes relevant for human breast cancer. The objective of the study was to compare (1) gene and protein expression and (2) mutation spectra of relevant human breast cancer genes between normal untreated mammary gland and mammary tumors from control and BDCA-exposed animals to identify molecular changes relevant for human cancer. Histologically, adenocarcinomas from control and BDCA-exposed animals were morphologically very similar, were estrogen/progesterone receptor positive, and displayed a mixed luminal/basal phenotype. Gene expression analysis showed a positive trend in the number of genes associated with human breast cancer, with proportionally more genes represented in the BDCA-treated tumor group. Additionally, a 5-gene signature representing possible Tgf beta pathway activation in BDCA-treated adenocarcinomas was observed, suggesting that this pathway may be involved in the increased incidence of mammary tumors in BDCA-exposed animals.