Environmental Chemical Body Burden and Prospective Breast Cancer Risk in the Cancer Prevention Study-3 Cohort

癌症预防研究 3 队列中的环境化学物质负担和潜在乳腺癌风险

• 批准号: 10669253
• 负责人: Susan L. Neuhausen
• 金额: $ 65.67万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-20 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669253
• 关键词: 3-Dimensional; Acceleration; Address; Age Years; Aging; American Cancer Society; Animals; Biological; Blood; Blood Banks; Blood specimen; Body Burden; Breast; Breast Cancer Risk Factor; Breast Cancer cell line; Breast Epithelial Cells; Cancer Control; Cancer Etiology; Carcinogenicity Tests; Case/Control Studies; Cells; Chemical Exposure; Chemicals; Cytokeratin; DNA Methylation; Data; Development; Diagnosis; Endocrine; Endocrine Disruptors; Enrollment; Environmental Exposure; Environmental Pollutants; Epithelial Cells; Epithelium; Etiology; Exposure to; Female; Foundations; Future; Genetic Transcription; Genome; Genomics; Goals; Health; Hormones; Human; Link; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Measurement; Measures; Methodology; Methylation; Molecular; Mus; Myoepithelial cell; Outcome; Participant; Perimenopause; Plasma; Poly-fluoroalkyl substances; Predisposition; Prevention strategy; Prospective Studies; Proteins; Research; Research Project Grants; Risk; Risk Factors; Role; Sampling; Seminal; System; Testing; Tissues; United States Environmental Protection Agency; Woman; Work; age related; aged; bead chip; breast cancer diagnosis; cancer diagnosis; cancer initiation; cancer prevention; cancer risk; cancer subtypes; carcinogenicity; case control; cohort; design; environmental chemical; epidemiology study; epigenome-wide association studies; in vivo; innovation; insight; interdisciplinary approach; interest; malignant breast neoplasm; mammary; mammary epithelium; methylome; multidisciplinary; polybrominated diphenyl ether; prospective; stem cells

Today there are more than 85,000 EPA-registered synthetic chemicals, but only 10% have been tested for carcinogenicity in animal studies. Of those tested, ~200 have shown evidence of causing cancer and/or an increase in mammary tumors. However, few of the chemicals have been evaluated in human studies, and results in humans have been inconclusive. Our study will focus on chemical body burden of per- and poly-fluoroalkyl substances (PFAS), and concomitant risk of developing invasive breast cancer during the menopausal transition. These “forever chemicals” are pervasive, enduring, and of high public interest, yet studies of their possible relationship to breast cancer have been limited. We hypothesize that elevated body-burden levels of these endocrine-disrupting chemicals (EDCs) will increase the risk of developing invasive breast cancer, and that alterations in DNA methylation (DNAm) and the breast microenvironment are mechanisms that link these chemical exposures and breast cancer. We will test this hypothesis using a three-pronged approach. In Specific Aim 1, we will conduct a prospective study of women in the American Cancer Society Cancer Prevention Study-3 (CPS-3) to assess the association between body burden of PFAS during the menopausal transition and subsequent development of invasive breast cancer. We will measure PFAS levels in plasma samples collected 1 to 7 years before invasive breast cancer diagnosis in 1000 CPS-3 participants and 1000 matched, cancer-free CPS-3 participants, all between 40 and 57 years of age at blood draw. In Specific Aim 2, studying the same participants, we will measure DNAm using Infinium MethylationEPIC BeadChips and conduct an epigenome- wide association study (EWAS) to identify DNAm changes associated with levels of PFAS in the cancer-free participants. We then will determine the association between the PFAS-associated DNAm changes and risk of developing breast cancer. This valuable DNAm data also can be used later for other outcomes, including exposure to other EDCs. In Specific Aim 3, we will determine the direct effects of PFAS on tissue- and molecular- level states associated with susceptibility to cancer initiation in genomically-well-characterized primary human breast mammary epithelial cells (HMECs). Identifying these mechanisms in primary breast cells is critically important, as PFAS mechanisms of action generally differ by tissue. We will use 2-D cultures to determine the effects of short-term exposures and 3-D cultures to define the effects of protracted chemical exposures on changes in epithelial lineage consistent with accelerated aging and age-related molecular changes in genome methylation, lineage-specific transcription, and cytokeratin proteins. Results from this multi-disciplinary approach will advance our understanding of the effects of PFAS exposures on risk of developing breast cancer during an important window of susceptibility. Ultimately, we hope results from our proposed project will identify an integrated biological signature of environmental exposure, deliver mechanistic insights into breast cancer development from EDCs, and inform future studies for prevention strategies to reduce or mitigate exposures.

如今，有超过 85,000 种在 EPA 注册的合成化学品，但只有 10% 经过了检测 动物研究中的致癌性。在接受测试的人中，约 200 人已显示出导致癌症和/或 乳腺肿瘤增加。然而，很少有化学物质经过人体研究评估，结果 在人类中尚无定论。我们的研究将重点关注全氟烷基和多氟烷基的化学负荷 物质（PFAS），以及绝经过渡期间发生浸润性乳腺癌的伴随风险。 这些“永远的化学物质”是普遍存在的、持久的，并且引起了公众的高度关注，但对其可能性的研究 与乳腺癌的关系有限。我们假设这些物质的身体负担水平升高 内分泌干​​扰化学物质（EDC）会增加患浸润性乳腺癌的风险，并且 DNA 甲基化 (DNAm) 和乳房微环境的改变是将这些联系起来的机制 化学物质暴露和乳腺癌。我们将使用三管齐下的方法来检验这个假设。具体来说 目标 1，我们将在美国癌症协会癌症预防研究 3 中对女性进行前瞻性研究 (CPS-3) 评估绝经过渡期间 PFAS 身体负担与 随后发展为浸润性乳腺癌。我们将测量收集的血浆样本中的 PFAS 水平 1000 名 CPS-3 参与者和 1000 名匹配的无癌症患者在诊断出浸润性乳腺癌前 1 至 7 年 CPS-3 参与者，抽血时年龄均在 40 岁至 57 岁之间。在具体目标 2 中，研究相同的 参与者，我们将使用 Infinium MmethylationEPIC BeadChip 测量 DNAm 并进行表观基因组- 广泛关联研究 (EWAS)，旨在确定无癌患者中与 PFAS 水平相关的 DNAm 变化 参与者。然后我们将确定 PFAS 相关 DNAm 变化与风险之间的关联 发展为乳腺癌。这些有价值的 DNAm 数据稍后还可用于其他结果，包括 接触其他 EDC。在具体目标 3 中，我们将确定 PFAS 对组织和分子的直接影响 与基因组特征良好的原代人类癌症发生易感性相关的水平状态 乳腺上皮细胞（HMEC）。识别原代乳腺细胞中的这些机制至关重要 重要的是，PFAS 的作用机制通常因组织而异。我们将使用二维文化来确定 短期暴露和 3D 培养的影响，以确定长期化学品暴露对 上皮谱系的变化与加速衰老和基因组中与年龄相关的分子变化一致 甲基化、谱系特异性转录和细胞角蛋白。这种多学科方法的结果 将加深我们对 PFAS 暴露对乳腺癌风险影响的理解 重要的易感性窗口。最终，我们希望我们提议的项目的结果能够确定一个 环境暴露的综合生物特征，提供对乳腺癌的机制见解 EDC 的发展，并为未来的预防策略研究提供信息，以减少或减轻暴露。