DIFFERENTIAL ACTIVATION OF HER BY MEKK1 IN TUMOR CELLS

他莫昔芬疗法在治疗肿瘤方面具有很大的潜力， 女性生殖组织不幸的是，许多肿瘤 对治疗有抵抗力并且独立生长。整体 本研究的目的是阐明其分子机制 雌激素在肿瘤细胞中的作用， 了解雌激素和抗雌激素的作用， 在临床上转化为更有效的抗- 雌激素治疗模型 雌激素和抗雌激素的作用是通过 雌激素受体（ER）。多项研究表明，ER可以 由非类固醇生长信号如肽生长因子激活。 生长因子受体和内质网之间的相互作用可能会刺激 ER阳性肿瘤的非依赖性生长，并有助于 这些肿瘤对他莫昔芬的耐药性。我们的初步调查显示 人ER在肿瘤细胞中被MEKK 1激活，MEKK 1可能参与了 来协调这个对话拟议研究的具体目标是 为了阐明激活的分子机制，进一步 表征激活的特异性，并检查 激活与非依赖性之间的函数关系 肿瘤生长和他莫昔芬抗性。 为了实现这些目标，从MEKK 1到ER的信号步骤将 通过生物化学方法进行解剖， 磷酸化和测定受体活性的存在下，或 缺乏已知的激酶活性或显性阴性形式， 由MEKK 1激活。ER激活的细胞特异性， 他莫昔芬敏感性和激素非依赖性卵巢、乳腺和子宫 将对肿瘤细胞进行分析和比较。最后，一个稳定的和可诱导的 MEKK 1显性阴性形式的表达将在 肿瘤细胞，以测试是否抑制内源性MEKK 1活性 阻断肿瘤细胞的激素非依赖性生长，并改变其 对他莫昔芬敏感

Tamoxifen therapy has great potential for the treatment of tumors of the female reproductive tissues. Unfortunately, many of the tumors are resistant to the therapy and grow hormone-independently. The overall objective of the proposed studies is to elucidate the molecular mechanism of estrogen action in the tumor cells with the hope that a better understanding about action of estrogens and anti-estrogens can be translated clinically into the development of a more effective anti- estrogen therapeutic model. The effects of estrogen and anti-estrogens are mediated through the estrogen receptor (ER). Multiple studies have shown that the ER can be activated by non-steroid growth signals such as peptide growth factors. The cross talk between growth factors receptors and the ER may stimulate the hormone-independent growth of ER-positive tumors and contribute to the resistance of these tumors to tamoxifen. Our preliminary indicate that the human ER is activated in tumor cells by MEKK1, which may be involved in mediating this cross talk. The specific aims of the proposed studies are to elucidate the molecular mechanism underlying the activation, to further characterize the specificity of the activation, and to examine the functional relationship between the activation and hormone-independent tumor growth and tamoxifen resistance. To achieve these objectives, the signaling steps from MEKK1 to the ER will be dissected by biochemical approaches involving in analyzing receptor phosphorylation and assaying the receptor activity in the presence or absence of either activity or dominant negative forms of kinases known to be activated by MEKK1. The cell specificity of the ER activation in tamoxifen-sensitive and hormone independent ovarian, breast and uterine tumor cells will be analyzed and compared. Finally, a stable and inducible expression of a dominant negative form of MEKK1 will be established in the tumor cells to test whether the inhibition of endogenous MEKK1 activity blocks the Hormone-independent growth of the tumor cells and changes their sensitivity to tamoxifen.