The Role of P27 in Breast Epithelial Progenitors and Breast Cancer Risk

P27 在乳腺上皮祖细胞和乳腺癌风险中的作用

• 批准号: 8633710
• 负责人: KORNELIA POLYAK
• 金额: $ 20.13万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633710
• 关键词: Age; Animal Model; Animals; Area; BRCA1 gene; Biological Markers; Biological Process; Biology; Breast; Breast Cancer Prevention; Breast Epithelial Cells; Bromodeoxyuridine; CD44 gene; Cell Culture Techniques; Cell Differentiation process; Cells; Characteristics; Chemoprevention; Data; Development; Epidemiology; Epigenetic Process; Epithelial; Epithelial Cell Proliferation; Estrogen receptor positive; Fatty acid glycerol esters; Female; Fibroblasts; Formalin; Frequencies; Gene Expression; General Population; Genes; Goals; Hormonal; Hormone Responsive; Human; Immunohistochemistry; Infertility; Knockout Mice; MME gene; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Methods; Modeling; Molecular Profiling; Mouse Mammary Tumor Virus; Mus; Myoepithelial; Paraffin Embedding; Pathway interactions; Play; Pregnancy; Prevention; Prevention strategy; Proliferating; Property; Research; Risk; Risk Marker; Role; Sampling; Signal Pathway; Signal Transduction; Slice; Stratification; TGFB1 gene; Testing; Time; Tissue Sample; Variant; Woman; base; breast tumorigenesis; cancer prevention; cancer risk; carcinogenesis; cell type; high risk; improved; in vivo; inhibitor/antagonist; malignant breast neoplasm; mammary epithelium; mutation carrier; parity; progenitor; self-renewal; stem; tumor initiation; tumorigenesis

Existing biomarkers and cancer prevention strategies are limited as the biology of breast tumor initiation remains poorly understood. We aim to elucidate mammary epithelial cells that participate in tumorigenesis as a means of developing markers for risk stratification and targets for prevention. Important clues to the identity of these cells come from epidemiologic and our preliminary data. Early full-term pregnancy is one of the most effective protections against breast cancer in most women but not in BRCA1/2 mutation carriers. We investigated parity-associated variation in gene expression profiles of distinct cell types in normal breast tissues of nulliparous and parous women. The most significant differences were seen in CD44+ cells where many genes important in self-renewal and differentiation (e.g., p27, TGFB) were lower in parous women than in nulliparous and in parous BRCA1/2 mutation carriers. The numbers of p27+ and Ki67+ cells were also significantly lower in parous than in nulliparous women except in parous BRCA1/2 cases. The majority of p27+ cells were also estrogen receptor positive. In explant cultures of breast tissues, inhibition of TGFB increased proliferation with a concomitant decrease of p27+ cells implying that p27 due to TGFB is key for keeping breast epithelial progenitors in a quiescent state. Based on these preliminary data, we hypothesize that (1) a subset of p27+ and Ki67+ cells represent quiescent and proliferating hormone-responsive breast epithelial progenitors, respectively, (2) p27 and TGFJ3 play an important role in keeping these progenitors quiescent, (3) the number of these progenitors correlates with breast cancer risk, and (4) mechanisms regulating p27+ progenitors are perturbed in BRCA1/2 mutation carriers and this contributes to their high risk. To test these hypotheses we propose: 1. To characterize the molecular profiles of p27+ and Ki67+ human breast epithelial cells from normal breast tissue of women with different risk of breast cancer. 2. To investigate the role of p27 and signaling pathways that regulates its expression in human breast epithelial cell proliferation and differentiation. 3. To characterize the role of p27 in regulating the abundance of mammary epithelial progenitors and its effect of this on mammary tumorigenesis in animal models.

现有的生物标志物和癌症预防策略是有限的，因为乳腺癌发生的生物学仍然知之甚少。我们的目的是阐明参与肿瘤发生的乳腺上皮细胞，作为开发风险分层标记和预防目标的手段。这些细胞身份的重要线索来自流行病学和我们的初步数据。早期足月妊娠对大多数女性来说是预防乳腺癌最有效的方法之一，但对BRCA1/2突变携带者来说并非如此。我们研究了未产和已产妇女正常乳腺组织中不同细胞类型的基因表达谱的胎次相关变异。最显著的差异出现在CD44+细胞中，其中许多在自我更新和分化中重要的基因（例如p27， TGFB）在分娩妇女中低于未分娩妇女和分娩BRCA1/2突变携带者。除已产BRCA1/2病例外，已产妇女的p27+和Ki67+细胞数量也显著低于未产妇女。大多数p27+细胞也呈雌激素受体阳性。在乳腺组织的外植体培养中，抑制TGFB增加了增殖，同时p27+细胞减少，这意味着TGFB导致的p27是保持乳腺上皮祖细胞处于静止状态的关键。基于这些初步数据，我们假设(1)p27+和Ki67+细胞分别代表静止和增殖激素应答的乳腺上皮祖细胞，(2)p27和TGFJ3在保持这些祖细胞静止中起重要作用，(3)这些祖细胞的数量与乳腺癌风险相关，(4)在BRCA1/2突变携带者中调节p27+祖细胞的机制受到干扰，这导致了它们的高风险。为了验证这些假设，我们提出：1。目的研究不同乳腺癌发病风险女性正常乳腺组织中p27+和Ki67+人乳腺上皮细胞的分子特征。2. 探讨p27及其表达调控信号通路在人乳腺上皮细胞增殖和分化中的作用。3. 在动物模型中表征p27在调节乳腺上皮祖细胞丰度中的作用及其对乳腺肿瘤发生的影响。