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

乳腺癌起源于上皮细胞；然而，乳腺癌的生长和 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与肿瘤 进展通常与荷尔蒙反应性的丧失有关。 由于荷尔蒙干预仍然是这两种疾病治疗的关键组成部分 乳腺癌和前列腺癌患者，有必要确定 荷尔蒙对荷尔蒙反应的肿瘤进展机制 不敏感的状态。我们最近已经证明， 前列腺癌细胞的雄激素非依赖性生长控制 获得替代的生长调节途径。我们相信类似的 生长因子/受体回路可能在转化过程中建立 乳腺上皮细胞在肿瘤进展过程中的作用。在这方面，IL-6已经 据报道能抑制几种人的体外增殖 乳腺癌细胞株。此外，我们有初步数据来 提示对类固醇敏感的乳腺上皮细胞正在生长 被IL-6抑制，而类固醇不敏感的上皮细胞， 相比之下，情况并非如此。因此，我们假设人类的乳房 癌细胞经历IL-6旁分泌功能的转变 肿瘤细胞生长过程中自分泌刺激因子的抑制作用 从类固醇敏感状态到类固醇不敏感状态。我们进一步 假设对类固醇受体有功能性依赖 与IL-6抑制乳腺生长相关的基因表达 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介导的乳房 癌细胞生长抑制，在体外，在这个应用中我们 建议测试这种有效的生长抑制物在阻断 乳腺癌细胞在体内生长。

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.