IL-6 & SIL-6R GROWTH INHIBITION OF BREAST CARCINOMA

白细胞介素6

• 批准号: 2414440
• 负责人: NITA J MAIHLE
• 金额: $ 19.6万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2414440
• 关键词: antisense nucleic acid; athymic mouse; autocrine; breast neoplasms; cell growth regulation; cytokine receptors; enzyme linked immunosorbent assay; estrogen receptors; estrogens; female; gene expression; growth inhibitors; hormone regulation /control mechanism; immunoprecipitation; interleukin 6; neoplasm /cancer transplantation; neoplastic growth; neoplastic process; progesterone receptors; receptor binding; receptor expression; steroid hormone receptor; tissue /cell culture; transfection

Breast carcinomas originate in epithelial cells; however, the growth and progression of these tumors is intimately related to the transformed epithelial cell's microenvironment. Steroidal sex hormones modulate the growth and differentiation of breast epithelial cells, and tumor progression is frequently associated with loss of hormone responsiveness. Since hormonal intervention remains a key component of treatment for both breast and prostate cancer patients, it is essential to determine the mechanisms underlying tumor progression from hormone responsive to hormone insensitive states. We have recently demonstrated that a key component of androgen independent growth control in prostate carcinoma cells is the acquisition of alternate growth regulatory pathways. We believe analogous growth factor/receptor circuits may become established in transformed breast epithelial cells during tumor progression. In this regard IL-6 has been reported to inhibit the in vitro proliferation of several human breast carcinoma cell lines. Furthermore, we have preliminary data to suggest that steroid sensitive breast epithelial cells are growth inhibited by IL-6, whereas steroid insensitive epithelial cells, in contrast, are not. We have, therefore, hypothesized that human breast carcinoma cells undergo a transition from IL-6 functioning as a paracrine inhibitor to an autocrine stimulator during the progression of tumor cells from a steroid sensitive to a steroid insensitive state. We further hypothesize that there is a functional dependence on steroid receptor expression that is correlated with IL-6 growth inhibition of breast epithelial cells. We have also demonstrated that a novel truncated form of the IL-6 receptor can dramatically potentiate IL-6 mediated breast carcinoma cell growth inhibition, in vitro, and in this application we propose to test the utility of this potent growth inhibitor in blocking breast carcinoma cell growth in vivo.

乳腺癌起源于上皮细胞;然而， 这些肿瘤的进展与转化的 上皮细胞的微环境 类固醇性激素调节 乳腺上皮细胞的生长和分化以及肿瘤 进展通常与激素反应性的丧失有关。 由于激素干预仍然是治疗的关键组成部分， 乳腺癌和前列腺癌患者，必须确定 激素对激素反应的肿瘤进展机制 麻木不仁的国家。 我们最近证明， 前列腺癌细胞中雄激素非依赖性生长控制是 获得替代的生长调节途径。 我们认为类似的 生长因子/受体回路可能在转化的 乳腺上皮细胞在肿瘤进展过程中。 在这方面，IL-6具有 据报道，它能抑制几种人类肿瘤细胞的体外增殖， 乳腺癌细胞系。 此外，我们有初步数据， 表明类固醇敏感乳腺上皮细胞正在生长 抑制IL-6，而类固醇不敏感的上皮细胞， 对比，没有。 因此，我们假设人类乳房 癌细胞经历从作为旁分泌的IL-6的转变， 肿瘤细胞进展过程中自分泌刺激物的抑制剂 从类固醇敏感到类固醇不敏感 我们进一步 假设存在对类固醇受体功能依赖性 与乳腺癌IL-6生长抑制相关的表达 上皮细胞 我们还证明了一种新的截断形式， IL-6受体可显著增强IL-6介导的乳腺癌 癌细胞生长抑制，在体外，在本申请中，我们 建议测试这种有效的生长抑制剂在阻断 乳腺癌细胞在体内的生长。