STROMA AND MAMMARY GLAND CELL PROLIFERATION

在之前的赠款期间，我们已经描绘了 正常小鼠乳腺对生长调节的反应性 雌激素(E)和孕酮(P)与卵巢癌个体发育的关系 雌激素(ER)和孕激素受体(PR)的细胞分布。 我们发现，反应性有一个连续的获得过程， 以使E诱导的增殖首先在3周时观察到 AGE，而E诱导PR和P诱导增殖被检测到 之后，在7周的时候。然而，ER最早在3日龄时就被检测到 在上皮和间质细胞中均有表达，缺乏增殖剂 这个年龄段的反应表明，非类固醇生长因子 可能是与生物相关的有丝分裂原和乳腺调节因子 体内腺体的生长和功能。在这方面，我们发现 表皮生长因子(EGF)可介导增殖效应 E在体内的早期发育。此外，在体外器官培养中， EGF+E治疗导致E-诱导物的早熟获得 公共关系此外，我们的研究表明，成人乳腺间质 也可导致未成熟的E-诱导型PR的早熟获得 3周龄的上皮细胞。因此，我们在 之前的授权期使我们现在处于有利地位，可以确定 介导上皮-间质细胞相互作用的分子机制 在正常的小鼠腺中获得荷尔蒙反应性。 我们假设1)特定生长因子(EGF， 转化生长因子-α、碱性成纤维细胞生长因子、胰岛素样生长因子-I、II)或生长抑制因子(转化生长因子-β)水平 上皮和/或间质细胞和/或2)特异性改变 细胞外基质(ECM)成分(I型、IV型胶原、层粘连蛋白、 纤维连接蛋白、Tenascin)与获得 体内对E和P的反应性。这些增长的每一个 因素/抑制物和ECM成分已被牵连到影响 乳腺的生长和功能。我们的目标将是测试 利用体内和体外研究这些变化的生物学相关性 接近了。详细分析了潜在的分子机制 导致转化的上皮-间质细胞相互作用 从荷尔蒙无反应状态到反应状态可能会导致新的 乳腺癌治疗的治疗策略。

In the previous grant period we have delineated the ontogeny of responsiveness of the normal mouse mammary gland to growth regulation by estrogen (E) and progesterone (P) in relation to the ontogeny of estrogen (ER) and progesterone receptor (PR) cellular distribution. We discovered that there is a sequential acquisition of responsiveness, such that E-inducible proliferation is observed first at 3 weeks of age, whereas E-inducible PR and P-inducible proliferation are detected later, at 7 weeks. However, ER are detected as early as 3 days of age in both epithelial and stromal cells and the lack of a proliferative response at this age indicates that non-steroidal growth factors are likely to be biologically relevant mitogens and regulators of mammary gland growth and function in vivo. In this regard, we find that epidermal growth factor (EGF) can mediate the proliferative effective of E at early ages in vivo. In addition, in vitro in organ culture, treatment with EGF+E causes the precocious acquisition of E-inducible PR. Furthermore, our studies demonstrate that adult mammary stroma also can cause the precocious acquisition of E-inducible PR in immature 3 week old epithelium. Thus the insights obtained by us in the previous grant period put us in a strong position to now determine the molecular mechanisms mediating epithelial-stromal cell interactions and the acquisition of hormonal responsiveness in the normal mouse gland. We hypothesize that 1) changes in specific growth factor (EGF, TGF-alpha, bFGF, IGF-I, II) or growth inhibitor (TGF-beta) levels in epithelial and/or stromal cells and/or 2) changes in specific extracellular matrix (ECM) components (collagen I, IV, laminin, fibronectin, tenascin) are correlated with the acquisition of responsiveness to E and P in vivo. Each of these growth factors/inhibitors and ECM components have been implicated to affect mammary gland growth and function. Our goal will be to then test the biological relevance of these changes using in vivo and in vitro approaches. Detailed analysis of the molecular mechanisms underlying the epithelial-stromal cell interactions which result in the transition from a hormonally non-responsive to a responsive state may lead to new therapeutic strategies for the treatment of breast cancer.