Environmental Arsenic in the Subtype Specification of Breast Cancer

乳腺癌亚型规范中的环境砷

• 批准号: 10252934
• 负责人: Marcelo G Bonini
• 金额: $ 35.42万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10252934
• 关键词: Acetylation; Agreement; Antioxidants; Archives; Arsenic; Bangladeshi; Biochemical; Breast; Breast Cancer Cell; Breast Cancer cell line; Carcinogens; Cell Count; Cell Culture Techniques; Cells; Chemoresistance; Chicago; Chronic; Collaborations; Colon Carcinoma; Development; Diffuse; Disease; Effectiveness; Enzymes; Estrogen Receptor alpha; Estrogen receptor negative; Estrogen receptor positive; Exposure to; Genetic; Histologic; Human; Hypoxia; In Situ; Incidence; Laboratories; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mammary Neoplasms; Mediating; Mitochondria; Molecular; Molecular Profiling; Mus; Neoplasm Metastasis; Oncoproteins; Patients; Pharmaceutical Preparations; Phenocopy; Phenotype; Physiological; Prevalence; Production; Reactive Oxygen Species; Recurrence; Renal carcinoma; Resistance; Risk; Risk Factors; Role; SOD2 gene; Signal Transduction; Sirtuins; Skin Cancer; Therapeutic; Tissues; Treatment Failure; Tumor Suppressor Proteins; Tumor Tissue; Universities; Woman; Xenograft Model; Xenograft procedure; base; cancer cell; cancer stem cell; cancer subtypes; cancer type; catalase; chemotherapy; drinking water; epidemiologic data; epidemiology study; exposed human population; gain of function; genetic manipulation; improved; in vivo; malignant breast neoplasm; malignant phenotype; mitochondrial metabolism; monomer; mouse model; mutant; neoplastic cell; personalized care; response; stem; stem cells; stem-like cell; stemness; therapy resistant; tumor; tumor initiation

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.

抽象的 环境无机砷（IAS）是I级人类致癌物，在 促进皮肤，结肠，膀胱和肾脏癌。 IAS作为乳腺癌的作用是 尽管许多研究表明，在细胞培养中，IAS促进了 乳腺癌细胞向雌激素受体负的表型的规格 这更具致命性和更多的治疗挑战。涉及的分子机制 仍然未知。我们的实验室发现，IAS促进了代谢的改变 线粒体活性氧（ROS）通过抑制肿瘤抑制剂sirtuin 3 导致乙酰化形式的锰超氧化物歧化酶（MNSOD）的积累 （MNSOD-AC），活性氧（ROS）增加和低氧诱导的激活 因子2α（HIF2α）。 HIF2α的激活是干细胞的公认机制 重新编程也已在转移性复发和治疗中暗示 乳腺癌女性的失败。因此，我们建议慢性IAS暴露是一种风险 通过涉及MNSOD的机制开发ER（ - ）乳腺癌的因素 乙酰化和线粒体ROS。通过扩展，我们提出MNSOD-AC/HIF2α 分子签名可能识别出暴露于IAS的乳腺癌的女性 对他们来说，所需的个性化护理会增加标准治疗失败的风险。还， MNSOD-AC/HIF2α可以针对这些女性的治疗。我们的目标是 如下：（1）确定MNSOD-AC是否将肿瘤细胞重编程为茎状（更具侵略性） 与化学抗性相关的表型和如果靶向MNSOD-AC会逆转此效果。 （2）确定饮用水中低水平的IAS暴露是否会转化ER+原位Xenograph 在小鼠中发育的肿瘤朝着更普遍的表型。 （3）确定是否有 暴露于IAS和乳腺癌与MNSOD-AC或MNSOD-ROS-之间的关联 HIF2α分子特征以及IAS暴露是否促进化学抗性或A 侵略性ER（ - ）表型的患病率。