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

现有的生物标记物和癌症预防策略是有限的，因为乳腺癌起始的生物学仍然知之甚少。我们的目标是阐明参与肿瘤发生的乳腺上皮细胞，作为开发风险分层和预防目标的标志的一种手段。有关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。在大多数女性中，早期足月怀孕是预防乳腺癌的最有效的保护措施之一，但在BRCA1/2突变携带者中则不然。我们研究了未产妇和临产妇女正常乳腺组织中不同细胞类型的基因表达谱与产次相关的差异。在CD44+细胞中差异最显著，其中许多对自我更新和分化重要的基因(如p27、TGFb)在产妇中低于未产妇和产妇BRCA1/2突变携带者。P27+和Ki67+细胞数除BRCA1/2外，其余均显著低于未产妇。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促进了增殖，同时伴随着p27+细胞的减少，这表明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的激素反应性乳腺上皮前体细胞，(2)p27和TGFJ3在保持这些前体细胞静止的过程中发挥重要作用，(3)这些前体细胞的数量与乳腺癌的风险相关，以及(4)在BRCA1/2突变携带者中，调节p27+前体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，我们建议：1.从不同乳腺癌风险的女性正常乳腺组织中鉴定p27+和Ki67+人乳腺上皮细胞的分子图谱。2.探讨p27及其调控信号通路在人乳腺上皮细胞增殖分化中的作用。3.研究p27基因在调控乳腺上皮祖细胞丰度中的作用及其在乳腺肿瘤发生中的作用。

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.