Environmental Arsenic in the Subtype Specification of Breast Cancer

乳腺癌亚型规范中的环境砷

• 批准号: 10488608
• 负责人: Marcelo G Bonini
• 金额: $ 35.64万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10488608
• 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) 是一种 I 类人类致癌物，已在以下方面发挥作用： 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 尽管大量研究表明，在细胞培养物中，iAs 可以促进 乳腺癌细胞向雌激素受体阴性表型的特化 这些疾病更致命，治疗起来也更具挑战性。涉及的分子机制 仍然未知。我们的实验室发现 iAs 促进新陈代谢的改变 通过抑制肿瘤抑制因子 Sirtuin 3 来抑制线粒体活性氧 (ROS) 导致乙酰化形式的锰超氧化物歧化酶 (MnSOD) 积累 (MnSOD-Ac)、活性氧 (ROS) 增加和缺氧诱导的激活 因子 2α (HIF2α)。 HIF2α 的激活是干细胞成熟的机制 重编程也与转移复发和治疗有关 患有乳腺癌的女性失败。因此，我们建议长期接触 iAs 是一种风险 通过涉及 MnSOD 的机制导致 ER(-) 乳腺癌发生的因素 乙酰化和线粒体 ROS。通过扩展，我们建议 MnSOD-Ac/HIF2α 分子特征可以识别暴露于 iAs 的患有乳腺癌的女性 需要个性化护理，因为他们标准治疗失败的风险增加。还， MnSOD-Ac/HIF2α 可以作为改善这些女性治疗的目标。我们的目标是 如下：（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） 与化疗耐药相关的表型，如果靶向 MnSOD-Ac 可以逆转这种效应。 (2) 确定饮用水中的低水平 iAs 暴露是否会改变 ER+ 原位异种移植图 小鼠体内的肿瘤向更普遍的表型发展。 (3)判断是否存在 暴露于 iAs 与乳腺癌与 MnSOD-Ac 或 MnSOD-ROS- 之间的关联 HIF2α 分子特征以及 iAs 暴露是否会促进化疗耐药性或 侵袭性 ER(-) 表型的流行。