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.

项目总结