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

现有的生物标志物和癌症预防策略是有限的，因为乳腺肿瘤发生的生物学仍然知之甚少。我们的目的是阐明乳腺上皮细胞参与肿瘤发生的一种手段，发展危险分层和预防目标的标志物。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。早期足月妊娠是大多数女性预防乳腺癌最有效的方法之一，但对BRCA 1/2突变携带者来说并非如此。我们研究了未经产和经产妇女正常乳腺组织中不同细胞类型基因表达谱的产次相关变异。在CD 44+细胞中观察到最显著的差异，其中许多基因在自我更新和分化中是重要的（例如，p27、TGFB）在经产妇女中低于未经产妇女和经产BRCA 1/2突变携带者。p27+和Ki 67+细胞的数量也显着低于初产妇女，除了在经产BRCA 1/2的情况下。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物中，TGFB的抑制增加了增殖，伴随着p27+细胞的减少，这意味着TGFB引起的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Ki 67+细胞的亚群分别代表静止和增殖的乳腺癌应答性上皮祖细胞，（2）p27和TGF β 3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）BRCA 1/2突变携带者中调节p27+祖细胞的机制受到干扰，这导致其高风险。为了验证这些假设，我们提出：1。研究不同乳腺癌风险女性正常乳腺组织中p27+和Ki 67+人乳腺上皮细胞的分子特征。2.探讨p27及其信号通路在人乳腺上皮细胞增殖和分化中的作用。3.研究p27在乳腺上皮祖细胞增殖中的作用及其对乳腺肿瘤发生的影响。

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.