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

项目摘要 这项建议的长期目标是减少发展为侵袭性三阴性乳腺癌的风险 癌症（TNBC），特别是非洲裔美国妇女（AAW），通过发现如何延长母乳喂养 保护乳房免受这种风险。AAW的母乳喂养率较低，这可能导致 TNBC发病率和死亡率较高。因此，我们的工作将专门针对乳房的这种差异， AAW面临的癌症后果。我们开发了独特的小鼠模型，用于研究逐渐退化（GI- 延长母乳喂养）与突然退化（AI-短母乳喂养）乳腺。我们已经表明 乳腺上皮细胞区室的细胞组成发生显著变化， 炎症标志物，重要的是在120天内观察到癌前增生性病变 在产后的人工智能腺中。这些癌前腺体高度表达转录因子Elf 5，这是一个关键的转录因子。 由管腔祖细胞（TNBC的起源细胞）表达的基因。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，增加炎症， 通过Elf 5介导的异常分化发展TNBC的风险更高：在本提案中，我们将使用 创新的方法，包括新的小鼠模型和患者样本，以描述 母乳喂养和TNBC。目的1A：描述GI与AI在人类乳腺癌小鼠模型中的保护作用 癌1B.确定阻断雌激素信号传导是否会消除AI诱导的增生性变化。我们 将使用MMTV-Cre; Brca 1fl/fl; p53 fl/fl小鼠和化学致癌物诱导模型来评估AI是否加速 TNBC的肿瘤发病率和进展。我们将用他莫昔芬治疗AI小鼠，以评估是否进展到 增生减轻。目的2：阐明Elf 5的作用和导致细胞凋亡的微环境（ME）的改变。 与AI乳腺癌前病变的关系我们将使用乳腺特异性Elf 5条件 敲除小鼠模型和用于该目的的体外方法。基因表达和CHIP-Seq将用于 识别Elf 5的下游效应子。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募集。目的3：观察组织学和 使用从母乳喂养的经产妇女获得的人乳腺组织在小鼠中观察到的分子变化 0-3（AI）对比> 6个月（GI）。我们将从Susan G.适用于Cure®纸巾的科门 Bank研究两个队列中胶原沉积和其他炎症标志物的差异。种族 还将评估差异。我们的工作对缩小 通过确定TNBC的新预防策略，在AAW中发现乳腺癌相关死亡率。此外，委员会认为， 这些研究将导致发现新的药物，可以帮助那些无法母乳喂养的妇女， 降低发展TNBC的风险。

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.