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.

摘要 环境无机砷(IAS)是一种I类人类致癌物质，在 促进皮肤癌、结肠癌、膀胱癌和肾癌。IAS作为一种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 乳腺癌细胞对雌激素受体阴性表型的特异性 它们的致命性更强，治疗起来也更具挑战性。其中涉及的分子机制 仍然不为人所知。我们的实验室发现，IAS促进了代谢的改变 线粒体活性氧(ROS)通过抑制肿瘤抑制基因Sirtuin 3 导致锰超氧化物歧化酶(MnSOD)以乙酰化形式积累 (MnSOD-Ac)、活性氧(ROS)升高和低氧诱导的激活 因子2α(α)。HIF2α的激活是干细胞的一种成熟机制 重新编程也被认为与转移复发和治疗有关 乳腺癌女性患者的失败。因此，我们认为长期接触ias是一种风险。 通过一种涉及MnSOD的机制促进ER(-)乳腺癌的发展 乙酰化和线粒体ROS。通过推广，我们提出了MnSODAc/Hif2α 分子标记可能识别曾接触过IAS和 需要个性化护理，因为他们标准治疗失败的风险增加。另外， MnSODAc/HIF2α可能是改善这些妇女治疗的靶点。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则逆转这一效应。 (2)确定饮用水中低水平的IAS暴露是否会转化ER+原位包裹体 小鼠体内的肿瘤向更普遍的表型发展。(3)确定是否有 暴露于IAS与携带MnSOD-Ac或MnSOD-ROS的乳腺癌的相关性 Hif2α分子特征以及iAS暴露是否促进化疗耐药或 侵袭性ER(-)表型的流行。