Addressing cancer disparity through defining the molecular link between breast feeding and triple negative breast cancer

通过定义母乳喂养与三阴性乳腺癌之间的分子联系来解决癌症差异

• 批准号: 10372950
• 负责人: Ramesh K. Ganju
• 金额: $ 43.5万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-06 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372950
• 关键词: Address; African American; BRCA1 gene; Breast; Breast Cancer Risk Factor; Breast Epithelial Cells; Breast Feeding; Cancer Death Rates; Caucasians; Cell Compartmentation; Cell Proliferation; Cells; ChIP-seq; Chronic; Collagen; Deposition; Development; Diagnosis; Epidemiologist; Epidemiology; Epithelial; Estrogen Antagonists; Estrogen receptor negative; Estrogens; FVB/N Mouse; Face; Gene Chips; Gene Expression Profiling; Genes; Gland; Global Change; Grant; Histologic; Human; Hyperplasia; In Vitro; Incidence; Inflammation; Inflammatory; Inflammatory Response; Knockout Mice; Lactation; Lesion; Link; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary gland; Mediating; Messenger RNA; Metaplasia; Methods; Modeling; Molecular; Mothers; Mouse Mammary Tumor Virus; Mus; Mutate; Oncogenic; Outcome; Pathway interactions; Patients; Phenotype; Population; Population Study; Postpartum Period; Pre-Clinical Model; Pregnancy; Premenopause; Prevalence; Prevention; Prevention strategy; Process; Proteins; Risk; Risk Factors; Role; Sampling; Signal Transduction; Study models; Tamoxifen; Therapeutic; Time; Tissue Banks; Tissues; Translating; Weaning; Woman; Work; base; black women; cancer health disparity; chemical carcinogen; cohort; conditional knockout; dimethylbenzanthracene; disparity reduction; epidemiology study; epithelial stem cell; high risk; human model; inflammatory marker; innovation; macrophage; malignant breast neoplasm; mammary; mammary epithelium; mortality; mouse model; mutation carrier; novel; parity; parous; premalignant; preventive intervention; progenitor; protective effect; racial difference; recruit; stem cells; transcription factor; translational impact; triple-negative invasive breast carcinoma; tumor; tumor initiation; tumor progression

PROJECT SUMMARY The long-term objective of this proposal is to reduce the risk of developing aggressive triple negative breast cancer (TNBC), especially for African-American women (AAW), by discovering how prolonged breastfeeding protects the breast from this risk. AAW have lower breastfeeding rates that likely contribute to the higher incidence of TNBC and higher mortality. Therefore, our work will specifically address this disparity in breast cancer outcomes faced by AAW. We developed unique mouse models for studying gradually involuting (GI- prolonged breastfeeding) vs abruptly involuting (AI-short breastfeeding) mammary glands. We have shown dramatic shifts in cellular composition of the mammary epithelial cell compartment and global changes in inflammatory markers and importantly have observed precancerous hyperplastic lesions within 120 days postpartum in the AI glands. These precancerous glands highly expressed the transcription factor Elf5, a key gene expressed by luminal progenitor cells, the cell-of-origin for TNBC. Based on these studies, we hypothesize that lack of breastfeeding not only alters the cellular composition and increases inflammation but leads to a higher risk of developing TNBC through Elf5 mediated aberrant differentiation: In this proposal, we will use innovative approaches including novel mouse models and patient samples to delineate the link between breastfeeding and TNBC. Aim 1A: Delineate the protective effects of GI vs. AI in mouse models of human breast cancer. 1B. determine if blocking estrogen signaling will abrogate the hyperplastic changes induced by AI. We will use MMTV-Cre;Brca1fl/fl;p53fl/fl mice and a chemical-carcinogen induced model to assess if AI accelerates tumor incidence and progression of TNBC. We will treat AI mice with tamoxifen to assess if progression to hyperplasia is mitigated. Aim 2: Elucidate the role of Elf5 and alterations in the microenvironment (ME) that led to the precancerous changes seen in the AI mammary glands. We will use mammary-specific Elf5 conditional knock-out mouse models and in vitro methods for this aim. Gene expression and CHIP-Seq will be utilized to identify the downstream effectors of Elf5. We will determine the differences in the ME between AI versus GI glands, especially the recruitment of different types of macrophages. Aim 3: Validate the histological and molecular changes observed in mice using human mammary tissue obtained from parous women who breastfed 0-3 (AI) vs. > 6 months (GI). We will obtain FFPE breast tissue from the Susan G. Komen for the Cure® Tissue Bank to study the differences in collagen deposition and other inflammatory markers in the two cohorts. Racial differences will also be evaluated. Our work has a high translational significance in reducing the disparity in breast cancer related mortality among AAW by identifying novel preventive strategies for TNBC. Furthermore, these studies will lead to discovery of novel agents that could help women who are unable to breastfeed to reduce the risk of developing TNBC.

项目概要 该提案的长期目标是降低患侵袭性三阴性乳腺癌的风险 癌症 (TNBC)，尤其是非裔美国女性 (AAW)，通过发现母乳喂养时间的长短 保护乳房免受这种风险。 AAW 的母乳喂养率较低，这可能导致母乳喂养率较高 TNBC 的发生率和死亡率较高。因此，我们的工作将专门解决乳房的这种差异 AAW 面临的癌症结果。我们开发了独特的小鼠模型来研究逐渐退化（GI- 长时间母乳喂养）与乳腺突然退化（AI-短母乳喂养）。我们已经展示了 乳腺上皮细胞区室的细胞组成发生巨大变化，并且整体变化 炎症标志物，重要的是在 120 天内观察到癌前增生性病变 产后的 AI 腺体。这些癌前腺体高度表达转录因子 Elf5，这是一个关键的转录因子。 由管腔祖细胞表达的基因，管腔祖细胞是 TNBC 的起源细胞。基于这些研究，我们假设 缺乏母乳喂养不仅会改变细胞组成并增加炎症，还会导致 通过 Elf5 介导的异常分化产生 TNBC 的风险更高：在本提案中，我们将使用 创新方法，包括新颖的小鼠模型和患者样本，以描绘之间的联系 母乳喂养和 TNBC。目标 1A：描述 GI 与 AI 在人类乳房小鼠模型中的保护作用 癌症。 1B.确定阻断雌激素信号传导是否会消除 AI 引起的增生性变化。我们 将使用 MMTV-Cre;Brca1fl/fl;p53fl/fl 小鼠和化学致癌物诱导模型来评估 AI 是否加速 TNBC 的肿瘤发生率和进展。我们将用他莫昔芬治疗 AI 小鼠，以评估是否进展为 增生减轻。目标 2：阐明 Elf5 的作用以及导致微环境 (ME) 的改变 AI 乳腺中观察到的癌前变化。我们将使用乳腺特异性 Elf5 条件 敲除小鼠模型和用于此目的的体外方法。基因表达和 CHIP-Seq 将用于 确定 Elf5 的下游效应器。我们将确定 AI 与 GI 之间 ME 的差异 腺体，特别是不同类型巨噬细胞的招募。目标 3：验证组织学和 使用从母乳喂养的经产妇女获得的人类乳腺组织在小鼠中观察到的分子变化 0-3 (AI) vs. > 6 个月 (GI)。我们将从 Susan G. Komen 处获取 FFPE 乳腺组织用于 Cure® Tissue 银行研究两个队列中胶原蛋白沉积和其他炎症标志物的差异。种族 还将评估差异。我们的工作对于缩小贫富差距具有重要的转化意义 通过确定新的 TNBC 预防策略，AAW 中乳腺癌相关死亡率。此外， 这些研究将导致新药物的发现，可以帮助无法母乳喂养的妇女 降低患 TNBC 的风险。