牛肉中残留Zeranol诱导人乳腺癌细胞增殖及激活STAT3信号通路的机制研究

Breast cancer is one of the most commonly diagnosed malignant tumors and the leading cause of cancer death in women. In recent years, the incidence of breast cancer is still increasing all over the world. Estrogen is one of the promoters of breast cancer, playing an important role during the initiation and development of breast cancer. The synthesized estrogens and/or xenoestrogens found in food products or environment, some of which are hormonally active and mimic estrogen, may have negative effect on human health and even induce mammary gland tumor. Therefore, more and more people pay attention to it. Zeranol is a non-steroidal, synthetic resorcyclic acid lactone compound with potent estrogen-like activity, as an anabolic growth promoter for widely use in the beef industry. Fusarium toxin zearalenone in contaminated cereals and feedstuffs also could be metabolized to Zeranol. Therefore, Zeranol may cause residues in cattle beef. However, the safety of using zeranol as a growth promoter has been debated for many years. Consumption of beef containing residues of zeranol and its metabolites may pose a breast cancer risk. Our previous studies have shown that Zeranol stimulated the proliferation of human breast cancer cell line MCF-7 and transfered normal breast cells to cancer cells in vitro. The current study focuses on the Zeranol containing in Zeranol-implanted beef, evaluates their adverse health risk to breast cancer cells from patient of different ages and body size, and tries to clear the mechanism of activation of STAT3 signaling pathway using the molecular biological methods under primary cultured human breast cancer cell model, cell co-culture system, tissue culture and animal model. This study aims to speedup the progress of evaluation of the safety of Zeranol containing in beef, to strengthen the understanding of the etiology of human breast cancer and provide rich data for risk evaluation as well as the carcinogenesis of synthesized estrogens and xenoestrogens exist in food, which provides a solid foundation for chemoprevention of human breast cancer.

乳腺癌是严重威胁女性生命健康最常见的恶性肿瘤之一。从食品中摄入外源类雌激素化合物可能是导致乳腺癌发病率不断升高的因素之一。Zeranol是一种具有雌激素效应的非固醇类化合物，常用于肉牛促生长，也可由存在于霉菌污染的饲料及其原料中的真菌毒素玉米赤霉烯酮加氢还原形成，所以很容易在牛肉组织中残留，然而，对其安全性还不明确。我们的前期研究发现，Zeranol能诱导人乳腺癌细胞系MCF-7的增殖以及引起正常乳腺细胞发生癌化，但对其作用机理以及牛肉中残留痕量Zeranol是否仍具有类雌激素效应和潜在的致乳腺癌作用还有待研究。本研究拟采用原代培养人乳腺癌单层细胞培养、细胞共培养、组织培养以及动物实验，研究牛肉中残留Zeranol对不同人群来源的乳腺癌细胞的增殖影响，并阐明其激活STAT3信号通路的作用机制。以期为Zeranol的膳食暴露风险评估提供参考，为乳腺癌高危人群的靶向预防提供理论依据。

乳腺癌是严重威胁人们生命健康的恶性肿瘤，是女性最常见的恶性肿瘤之一，位居女性恶性肿瘤发病率和死亡率的首位。乳腺癌的发生原因非常复杂，可能与遗传、环境、饮食等多因素有关，而其中雌激素是这些因素背后直接与乳腺癌相关的一个因子。Zeranol是一种具有雌激素效应的非固醇类化合物，常用于肉牛促生长，也可由存在于霉菌污染的饲料及其原料中的真菌毒素玉米赤霉烯酮加氢还原形成，容易在动物组织中残留，然而，长期以来对其安全性还不明确。本研究采用原代培养人乳腺癌单层细胞培养、细胞共培养、组织培养模型以及动物实验，研究了Zeranol对乳腺癌细胞的增殖以及相关信号通路基因表达的影响。结果表明，Zeranol能促进雌激素受体阳性乳腺癌细胞的增殖，但对雌激素受体阴性乳腺癌细胞无明显影响，Zeranol具有雌激素样活性，其促增殖作用可能是通过雌激素受体(ER)信号通路所介导；Zeranol可以促进前脂肪细胞的增殖、上调前脂肪细胞中芳香化酶mRNA和蛋白的表达水平以及诱导雌激素E2的产生，造成微环境中局部雌激素升高，引起细胞增殖与凋亡相关基因的变化，例如上调cyclinD1、Bcl-2基因的表达，下调Bax基因的表达，从而诱导乳腺癌上皮细胞的进一步增殖。本研究为Zeranol的安全风险评估提供一定的参考。