NEW ENDOCRINE THERAPY IN OLDER WOMEN WITH BREAST CANCER

内分泌疗法通常用于乳腺癌的治疗。 绝经后妇女，尤指年龄最大的病人。 内分泌治疗的疗效取决于对 雌激素和多肽生长因子对乳腺细胞生长的影响。然而， 随着乳腺癌的发展，这种疾病通常会对 雌激素，大多数患者对治疗不再有效 抗雌激素。新的数据表明，生长调节功能 随着HER-2的扩增，癌细胞中的雌激素被破坏 生长因子受体。HER-2的过度表达发生在25%-30%的 绝经后妇女的乳腺癌，并与 内分泌治疗在临床上的失败。理解生物学 这一协会的基础可能有助于改善管理和 提高患者存活率。该项目的具体目标是：i) 确认HER-2受体过表达在促进中的作用 雌激素非依赖性生长，并研究替代疗法 在临床前模型中预防人类乳腺癌的进展 绝经后乳腺癌。亲代乳腺癌细胞具有低- 高表达HER-2和生物工程子代细胞的研究 HER-2的表达将测试其对 雌激素，他莫昔芬和纯抗雌激素。此外，我们还将评估 联合抗雌激素治疗的治疗优势 下调HER-2受体的抗受体抗体。 2)探讨雌激素受体的调控机制 (Er)通过生长因子受体信号通路。这项研究将 关注HER-2受体的信号转导及其潜能 下游对野生型和变异型ER，On转录的影响 雌激素受体与雌激素反应元件的结合和相互作用 细胞核，以及内质网酪氨酸和丝氨酸残基的磷酸化 在乳腺癌细胞中。针对ER mRNA的反义寡核苷酸将被 用于定义ER在HER-2促进生长中的可能作用。 3)评估HERG的生物学意义，它是一种 HER-2/HER-3受体激活在乳腺癌进展中的作用 以及不依赖雌激素的生长。Heregulins可能是雌激素诱导的 增长因素。这一假说将通过测量荷尔蒙来检验。 HERG基因转录和分泌的调控及其机制 甘草酸对绝经后细胞生长影响的研究 病人。抗疱疹病毒蛋白抗体也将被评估为新的 抗肿瘤药物。 这些研究可能会为老年女性带来新的激素疗法。 她-过度表达乳腺癌。

Endocrine therapy is commonly used for treatment of breast cancer in postmenopausal women, especially among patients of the oldest age. The efficacy of endocrine treatment depends on close regulation of breast cell growth by estrogens and peptide growth factors. However, as breast cancer progresses, the disease usually becomes resistant to estrogens, and most patients no longer respond to therapy with antiestrogens. New data show that the growth-regulatory function of estrogens is disrupted in cancer cells with amplification of HER-2 growth factor receptors. Overexpression of HER-2 occurs in 25-30% of breast cancers in postmenopausal women and is associated with the failure of endocrine therapy in the clinic. Understanding the biologic basis of this association may help to improve management and increase patient survival. Specific aims of this project are: I) To confirm the role of HER-2 receptor overexpression in the promotion of estrogen-independent growth and to investigate alternate treatments to prevent human breast cancer progression in preclinical models of postmenopausal breast cancer. Parent breast cancer cells with low- expression of HER-2 and bioengineered daughter-cells with high- expression of HER-2 will be tested for their differential sensitivity to estrogen, tamoxifen and pure antiestrogen. In addition, we will assess the therapeutic advantage of antiestrogen therapy in combination with antireceptor antibodies which down-regulate the HER-2 receptor. 2)To investigate the mechanism for regulation of estrogen receptor (ER) by a growth factor receptor signaling pathway. The study will focus on signal transduction by HER-2 receptor and potential downstream effects on transcription of wild-type and variant ER, on binding and interaction of ER with estrogen-response elements in the nucleus, and on phosphorylation of tyrosine and serine residues in ER in breast cancer cells. Antisense oligonucleotide to ER mRNA will be used to define the possible role-of ER in HER-2-promoted growth. 3)To assess the biologic significance of heregulin, a ligand for activation of HER-2/HER-3 receptors, in breast cancer progression and estrogen-independent growth. Heregulins may be estrogen-induced growth factors. This hypothesis will be tested by measure of hormonal modulation of heregulin mRNA transcription and secretion and by study of heregulIn effects on growth of cells from postmenopausal patients. Anti-heregulin antibodies will also be evaluated as novel antitumor agents. These studies may lead to new hormone therapies in older women with HER-overexpressing breast cancers.