Environmental Arsenic in the Subtype Specification of Breast Cancer

摘要 环境无机砷（iAs）是一类人类致癌物， 促进皮肤癌、结肠癌、膀胱癌和肾癌。iAs作为乳腺癌致癌物的作用是 虽然许多研究表明，在细胞培养中，iAs促进了 乳腺癌细胞向雌激素受体阴性表型的特化 这是更致命的，也更具有挑战性的治疗。涉及的分子机制 仍然未知。我们的实验室发现，iAs促进代谢的改变， 线粒体活性氧（ROS）通过抑制肿瘤抑制因子Sirtuin 3， 导致锰超氧化物歧化酶（MnSOD）以乙酰化形式积累 （MnSOD-Ac），增加活性氧（ROS）和激活缺氧诱导的 因子2α（HIF 2 α）。HIF 2 α的激活是干细胞分化的一个公认机制， 重编程也与转移复发和治疗有关， 女性乳腺癌的治疗失败。因此，我们认为长期接触iAs是一种风险， 通过涉及MnSOD的机制促进ER（-）乳腺癌发展的因素 乙酰化和线粒体ROS。通过推广，我们提出MnSOD-Ac/HIF 2 α 分子特征可以识别暴露于iAs的乳腺癌女性， 他们需要个性化的护理，因为标准治疗失败的风险增加。还有， MnSOD-Ac/HIF 2 α可能是改善这些女性治疗的靶点。我们的目标是 （1）确定MnSOD-Ac是否将肿瘤细胞重编程为干细胞样（更具侵袭性） 与化学抗性相关的表型，并且如果靶向MnSOD-Ac则逆转该效应。 (2)确定饮用水中的低水平iAs暴露是否会转化ER+原位异种移植物 肿瘤在小鼠中向更普遍的表型发展。(3)确定是否存在 暴露于iAs和乳腺癌之间的关联与MnSOD-Ac或MnSOD-ROS- HIF 2 α分子特征以及iAs暴露是否促进化疗耐药性或 侵袭性ER（-）表型的患病率。

ABSTRACT Environmental inorganic arsenic (iAs) is a class I human carcinogen with established roles in promoting skin, colon, bladder and kidney cancers. The role of iAs as a breast carcinogen is less established although numerous studies have indicated that in cell cultures iAs promotes the specification of breast cancer cells towards phenotypes that are estrogen receptor negative which are more lethal as well as more challenging to treat. The molecular mechanisms involved remain unknown. Our laboratory found that iAs promotes alterations in the metabolism of mitochondrial reactive oxygen species (ROS) via inhibiting the tumor suppressor Sirtuin 3 which leads to the accumulation of manganese superoxide dismutase (MnSOD) in an acetylated form (MnSOD-Ac), increased reactive oxygen species (ROS) and the activation of hypoxia induced factor 2α (HIF2α). The activation of HIF2α is a well-established mechanism of stem cell reprogramming that has also been implicated in metastatic recurrence as well as treatment failure in women with breast cancer. Hence, we propose that chronic iAs exposure is a risk factor for the development of ER(-) breast cancer via a mechanism that involves MnSOD acetylation and mitochondrial ROS. By extension, we propose that the MnSOD-Ac/HIF2α molecular signature may identify women with breast cancer that have been exposed to iAs and required personalized care for they are at increased risk of failing standard therapeutics. Also, that the MnSOD-Ac/HIF2α may be targeted to improve therapy in these women. Our aims are as follows: (1) determine if MnSOD-Ac reprograms tumor cell to stem-like (more aggressive) phenotypes associated with chemoresistance and if targeting MnSOD-Ac reverses this effect. (2) determine if low level iAs exposure in the drinking water transforms ER+ in situ xenograph tumors developing in mice towards more pervasive phenotypes. (3) determine if there is an association between exposure to iAs and breast cancer with a MnSOD-Ac, or MnSOD-ROS- HIF2α molecular signature as well as if iAs exposure promotes chemoresistance or a prevalence of aggressive ER(-) phenotypes.