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

项目总结 这项建议的长期目标是降低发生侵袭性三重阴性乳房的风险。 癌症(TNBC)，特别是对非裔美国妇女(AAW)，通过发现延长母乳喂养如何 保护乳房免受这种风险。Aaw的母乳喂养率较低，这可能是导致 TNBC的发病率和较高的死亡率。因此，我们的工作将专门解决乳房的这种差异 AAW面临的癌症后果。我们开发了独特的小鼠模型来研究渐进性退化(GI- 长时间母乳喂养)与突然退化(AI-短暂母乳喂养)的乳腺。我们已经展示了 乳腺上皮细胞室细胞组成的戏剧性变化和全球变化 炎性标志物和重要的是在120天内观察到癌前增生性病变 产后人工智能腺体。这些癌前病变腺体高度表达转录因子ELF5，这是一种关键 由腔祖细胞表达的基因，它是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，增加炎症，还会导致 通过ELF5介导的异常分化发生TNBC的风险更高：在本提案中，我们将使用 包括新的小鼠模型和患者样本在内的创新方法来描述 母乳喂养和TNBC。目的1A：比较GI和AI对小鼠人乳腺模型的保护作用 癌症。1B.确定阻断雌激素信号是否会消除AI诱导的增生性改变。我们 将使用MMTV-Cre；Brca1fl/fl；p53fl/fl小鼠和化学致癌物诱导的模型来评估AI是否加速 肿瘤的发病率和TNBC的进展。我们将用他莫昔芬治疗AI小鼠，以评估是否进展到 增生性疾病减轻。目的2：阐明ELF5的作用和导致微环境(ME)的变化 人工智能乳腺中出现的癌前病变。我们将使用特定于乳房的ELF5条件 为此目的的基因敲除小鼠模型和体外方法。基因表达和芯片序列将用于 确定ELF5的下游效应器。我们将确定AI和GI在ME方面的差异 腺体，尤其是不同类型巨噬细胞的募集。目标3：验证组织学和 用母乳喂养产妇的人乳腺组织观察小鼠的分子变化 0-3(人工智能)与6个月(GI)。我们将从Susan G.Komen那里获得FFPE乳房组织，用于Cure®组织 Bank研究两组患者在胶原沉积和其他炎症标志物方面的差异。种族 还将对差异进行评估。我们的工作对缩小中美之间的差距具有很高的翻译意义。 通过确定新的TNBC预防策略，在AAW中研究乳腺癌相关死亡率。此外， 这些研究将导致发现新的制剂，可以帮助无法母乳喂养的妇女 降低发展跨国公司的风险。

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.