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: 10590700
• 负责人: Ramesh K. Ganju
• 金额: $ 43.78万
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590700
• 关键词: Acceleration; Address; African American; American; Anthracenes; 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; Disparity; Epidemiologist; Epidemiology; Epithelium; Estrogen Antagonists; Estrogen receptor negative; Estrogens; FVB/N Mouse; Face; Gene Chips; Gene Expression; Gene Expression Profiling; Genes; Gland; Global Change; Grant; Histologic; Human; Hyperplasia; In Vitro; Incidence; Inflammation; Inflammatory; Inflammatory Response; Knockout Mice; Lactation; Lesion; Link; Macrophage; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary gland; Mediating; Messenger RNA; Metaplasia; Methods; Modeling; Molecular; Mothers; Mouse Mammary Tumor Virus; Mus; Mutate; Neoplasm Metastasis; 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; Risk Reduction; Role; Sampling; Signal Transduction; Study models; Tamoxifen; Therapeutic; Time; Tissue Banks; Tissues; Translating; Weaning; Woman; Work; black women; cancer health disparity; cancer subtypes; chemical carcinogen; cohort; conditional knockout; dimethylbenzanthracene; disparity reduction; epidemiology study; epithelial stem cell; high risk; human model; inflammatory marker; innovation; malignant breast neoplasm; mammary; mammary epithelium; mortality; mouse model; mutation carrier; novel; parity; parous; post pregnancy; 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.

项目摘要 该提议的长期目标是降低发展侵略性三重负乳房的风险 癌症（TNBC），特别是对于非裔美国妇女（AAW），通过发现如何长时间母乳喂养 保护乳房免受这种风险。 AAW的母乳喂养率较低，可能导致更高 TNBC的发生率和更高的死亡率。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，用于研究逐渐参与的（gi-） 长时间的母乳喂养）与突然涉及（AI-Short母乳喂养）乳腺的乳腺。我们已经显示了 乳腺上皮细胞室细胞组成的急剧变化和全球变化 炎症标记和重要的是在120天内观察到癌前的增生性病变 AI腺产后。这些癌前腺高度表达了转录因子ELF5，这是一个钥匙 由腔祖细胞表达的基因，TNBC的原始细胞。基于这些研究，我们假设 缺乏母乳喂养不仅改变了细胞组成并增加了感染，还会导致 通过ELF5介导的异常差异化开发TNBC的风险更高：在此提案中，我们将使用 创新方法包括新型鼠标模型和患者样品，以描绘 母乳喂养和TNBC。 AIM 1A：在人乳房的小鼠模型中描述GI与AI的保护作用 癌症。 1B。确定阻断雌激素信号是否会消除AI诱导的增生变化。我们 将使用mmtv-cre; brca1fl/fl; p53fl/fl小鼠和化学 - car霉素诱导的模型来评估AI是否加速 TNBC的肿瘤发生率和进展。我们将使用他莫昔芬对AI小鼠进行治疗，以评估进展是否 减少增生。 AIM 2：阐明ELF5的作用和带领的微环境（ME）的改变 在AI乳腺中看到的癌前变化。我们将使用有条件的乳腺特异性ELF5 敲除小鼠模型和该目标的体外方法。基因表达和chip-seq将用于 确定ELF5的下游效应。我们将确定AI与GI之间的ME差异 腺体，特别是募集不同类型的巨噬细胞。目标3：验证组织学和 在小鼠中使用从母乳喂养的帕洛斯妇女获得的人类乳腺组织观察到的分子变化 0-3（AI）与> 6个月（GI）。我们将从Susan G. Komen获得Cure®组织的FFPE乳房组织 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。我们的工作在减少差异方面具有很高的翻译意义 通过鉴定TNBC的新型预防策略，AAW与乳腺癌相关的死亡率。此外， 这些研究将导致发现新颖的特工，这些新药物可以帮助无法母乳喂养的女性 降低开发TNBC的风险。