TGFb Regulation of ER Receptor Positive Mammary Cells

描述(申请人提供)：转化生长因子β1(转化生长因子β1)被广泛认为是一种有效的抑制人和小鼠乳腺上皮细胞增殖的药物。我们已经定位了它在小鼠乳腺中的活性，并描述了Tgfbeta1杂合子小鼠的增殖表型：两者都受到卵巢激素雌激素和孕酮的调节。众所周知，雌激素通过雌激素受体传递信号？(ER)在乳腺上皮细胞增殖中起核心作用。最近的一些研究表明，大多数雌激素受体阳性(ER+)细胞不会增殖，但需要通过旁分泌机制来调节ER-细胞的增殖。维持增殖能力的ER+细胞亚群很小(在人和小鼠乳腺中约为1%)，被认为是ER+乳腺癌的早期祖细胞。我们发现，发情期小鼠乳腺中几乎所有的ER+细胞都与强烈的转化生长因子-β活性共存，这与它们的非增殖状态一致。然而，在Tgfbeta1杂合子乳腺中，ER+细胞的增殖增加了2倍以上，这进一步导致ER+细胞总数比野生型乳腺上皮增加了30%。基于这些观察，我们假设转化生长因子-β积极抑制乳腺上皮细胞的增殖，特别是调节被推测为代表谱系限制性祖细胞的ER+细胞亚群。在干细胞/前体细胞是致癌靶点的程度上，我们进一步假设转化生长因子-β作用的中断与ER+乳腺癌的发生有关。因此，我们的总体目标是将转化生长因子-β1与ER+复制细胞数量之间的功能关系定义为年龄的函数。提出了三个目标：1：确定ER+细胞的频率与转化生长因子-β1水平、定位和活性的函数关系。2：分析转化生长因子-β对乳腺干细胞复制能力的影响。3：确定ER+亚群的转化生长因子-β调节是否与癌前病变的进展和/或特征有关。

DESCRIPTION (provided by applicant): Transforming growth factor beta1 (TGF-beta) is widely acknowledged as a potent inhibitor of human and mouse mammary epithelial proliferation. We have localized its activity in the mouse mammary gland and characterized the proliferative phenotype of the Tgfbeta1 heterozygote mouse: both are regulated by the ovarian hormones estrogen and progesterone. It is well known that estrogen signaling through estrogen receptor ? (ER) plays a central role in mammary epithelial cell proliferation. Several recent studies have shown that the majority of estrogen receptor-positive (ER+) cells do not proliferate, but are required to regulate proliferation in ER-negative (ER-) cells via paracrine mechanisms. The small subpopulation (approximately 1% in human and mouse breast) of ER+ cells that maintain proliferative potential has been postulated to be early progenitor cells that could be the origin of ER+ breast cancer. We found that nearly all of the ER+ cells in mouse mammary gland at estrus co-localize with intense TGF-beta activity, consistent with their non-proliferative status. However, proliferation of ER+ cells is increased more than 2-fold in Tgfbeta1 heterozygote mammary gland, which furthermore resulted in a 30% increase in the total number of ER+ cells compared to wildtype mammary epithelium. Based on these observations we hypothesize that TGF-beta actively restrains proliferation of mammary epithelial cells and, in particular, regulates the subpopulation of ER+ cells that are speculated to represent lineage-restricted progenitor. To the extent that stem cells/progenitors are targets for carcinogenesis, we further hypothesize that disruption of TGF-beta action is involved in the genesis of ER+ breast cancer. Our overall goal, therefore, is to define the functional relationship between TGF-beta1 and the population of ER+ replicative cells as a function of age. Three aims are proposed: 1: To determine the frequency of ER+ cells as a function of TGF-beta1 level, localization and activity. 2: To analyze TGF-beta effects on the replicative potential of presumptive mammary stem cells. 3: To determine whether TGF-beta regulation of the ER+ subpopulation contributes to progression and/or features of preneoplastic lesions.