STROMA AND MAMMARY GLAND CELL PROLIFERATION

基质和乳腺细胞增殖

• 批准号: 2090117
• 负责人: SANDRA Z HASLAM
• 金额: $ 16.25万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-07-01 至 1998-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2090117
• 关键词: autoradiography; breast neoplasms; cell cell interaction; cell cycle; cell growth regulation; epidermal growth factor; estrogen receptors; estrogens; extracellular matrix; fibroblast growth factor; growth factor; growth factor receptors; growth inhibitors; hormone receptor; hormone regulation /control mechanism; hormone related neoplasm /cancer; immature animal; immunocytochemistry; insulinlike growth factor; laboratory mouse; mammary epithelium; mammary gland; mitogens; progesterone; progesterone receptors; stromal cells; tissue /cell culture; transforming growth factors

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.

在前一个赠款期间，我们已经描绘了个体发育的 正常小鼠乳腺对生长调节的反应性 雌激素（E）和孕激素（P）与个体发育的关系 雌激素（ER）和孕激素受体（PR）的细胞分布。 我们发现，反应能力的获得是有顺序的， 这样，E-诱导的增殖首先在3周时观察到， 年龄，而检测到E-诱导PR和P-诱导增殖 7周后。 然而，ER早在3日龄时就被检测到 在上皮细胞和基质细胞中， 在这个年龄的反应表明，非甾体生长因子是 可能是生物学相关的有丝分裂原和乳腺癌的调节因子， 腺体生长和功能。在这方面，我们发现， 表皮生长因子（EGF）可介导增殖效应， E在体内的早期年龄。 此外，在体外器官培养中， EGF+E治疗导致E-诱导的早熟获得， PR. 此外，我们的研究表明，成人乳腺间质 也可以导致未成熟的E-inducible PR的早熟获得， 3周龄上皮。 因此，我们在 上一个赠款期使我们处于有利地位，现在确定 介导上皮-基质细胞相互作用的分子机制， 在正常小鼠腺体中获得激素反应性。 我们假设1）特异性生长因子（EGF， 中的TGF-α、bFGF、IGF-I、II）或生长抑制剂（TGF-β）水平 上皮和/或基质细胞和/或2）特异性 细胞外基质（ECM）成分（胶原I，IV，层粘连蛋白， 纤维连接蛋白，腱生蛋白）与获得 体内对E和P的反应性。 每一次增长 因子/抑制剂和ECM成分已经被牵连到影响 乳腺生长和功能。 我们的目标是测试 这些变化的生物学相关性使用体内和体外 接近。 详细分析潜在的分子机制 上皮-基质细胞的相互作用导致了 从生理上无响应到响应状态可能导致新的 治疗乳腺癌的治疗策略。