STEROID RECEPTOR ACTIVATION PATHWAYS IN THE MAMMARY GLAND

乳腺发育和肿瘤发生受激素和生长的影响 细胞因子信号，其响应由细胞内和细胞外的 膜受体 细胞内受体的参与 雌激素和孕激素在这些过程的调节是很好的 记录在案。 雌孕激素受体在乳腺癌中的作用 组织受受体本身的组成和 因素（激素等）调节它们的转录调节 活动 为 例如，雌激素的转录后变体， 孕酮受体已被鉴定为显示出功能改变， 相对于野生型受体的活性。 其中一些表达 在乳腺癌细胞中的变异增加。 这些活动 变异明显影响雌激素的总体活性， 孕酮受体 第二，我们和其他人已经表明， 雌激素和孕激素的类固醇受体的活性，可以是 在缺乏S特异性甾体配体的情况下， 信号包括刺激细胞内 磷酸化途径。 我们的研究结果表明，这些受体可能 提供了激素和非激素信号传导的共同介质， 这些通路汇聚在一起调节靶基因的表达， 影响乳腺细胞表型。 本提案的总体目标是审查 雌激素和孕激素受体组成和途径的贡献 用于激活乳腺癌致瘤难治状态的受体 高剂量雌激素和孕激素治疗诱导的组织。 实现总体目标的具体目标如下。 第一章 建立野生型和变异型雌激素的定量互补 大鼠乳腺上皮和间质组织中孕酮受体的表达 在乳腺发育期间，在MNU诱导的肿瘤发生期间和之后， 诱导乳腺状态，该乳腺状态对癌发生是难治性的， 雌激素和孕激素治疗; 2）建立功能性 雌激素和孕激素受体变异体在体外和 雌激素和孕激素受体阴性细胞培养。 3)到 确定雌激素的时间和空间表达， 孕激素受体调控的靶基因是年龄、激素和生长 因子调节，并确定难治性乳腺表型是否 早期服用雌激素和孕激素引起的， 伴随着这些目标的后续反应的改变， 雌激素或孕激素受体的基因可以直接导致 大鼠乳腺组织的致癌潜力。 这些研究将 提供了有价值的新见解的生化机制， 乳腺癌的发生以及预防肿瘤发生 雌激素和孕激素。

Breast development and tumorigenesis are influenced by hormonal and growth factor signals whose responses are mediated by intracellular and cell membrane receptors. The involvement of intracellular receptors for estrogen and progesterone in the regulation of these processes is well documented. The function of estrogen and progesterone receptors in mammary tissue is influenced by the composition of the receptors themselves and by the factors (hormones, etc.) that regulate their transcriptional regulatory activity. For example, post-transcriptional variants of estrogen and progesterone receptors have been identified that display altered functional activity relative to wild-type receptors. The expression of some of these variants is increased in breast cancer cells. The activity of these variants clearly influences the overall activity of estrogen and progesterone receptors. Secondly, we and others have shown that the activity of steroid receptors for estrogen and progesterone, can be activated in the absence of a s specific steroidal ligand by extracellular signals including growth factors that stimulate intracellular phosphorylation pathways. Our results suggest that these receptors may provide common mediators through which hormone and non-hormone signaling pathways converge to regulate the expression of tar get genes that influence mammary cellular phenotype. The overall objective of this proposal is to examine the mechanistic contribution of estrogen and progesterone receptor composition and pathways for activation of receptors to the oncogenic refractory state in mammary tissue which is induced by high dose estrogen and progesterone treatment. The specific aims to accomplish the overall objectives are as follows. 1) To establish the quantitative complement of wild-type and variant estrogen and progesterone receptors in rat mammary epithelial and stromal tissue during mammary development, during MNU-induced tumorigenesis and after induction of a mammary state that is refractory to carcinogenesis by early treatment with estrogen and progesterone; 2) To establish the functional capacity of estrogen and progesterone receptor variants in vitro and in estrogen and progesterone receptor negative cell cultures.; 3) To determine whether the temporal and spatial expression of estrogen and progesterone receptor regulated target genes is age, hormone and growth factor regulated and to establish whether the refractory mammary phenotype that is induced by early administration of estrogen and progesterone is accompanied by alterations in the subsequent responses of these target genes to estrogen, or progesterone receptor can directly contribute to the oncogenic potential of rat mammary tissue. Together, these studies will provide valuable new insight into the biochemical mechanisms that underlie mammary carcinogenesis as well as th prevention of tumorigenesis by estrogen and progesterone.