NEW ENDOCRINE THERAPY IN OLDER WOMEN WITH BREAST CANCER

老年乳腺癌女性的新内分泌治疗

• 批准号: 2395145
• 负责人: Richard Joseph Pietras
• 金额: $ 11.65万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-15 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2395145
• 关键词: antireceptor antibody; antisense nucleic acid; athymic mouse; biological signal transduction; breast neoplasms; cancer prevention; disease /disorder model; estrogen inhibitor; estrogen receptors; female; growth factor receptors; hormone therapy; ligands; neoplastic process; nonhuman therapy evaluation; phosphorylation; postmenopause; receptor expression; receptor sensitivity

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.

内分泌疗法通常用于治疗乳腺癌， 绝经后妇女，尤其是年龄最大的患者。 内分泌治疗的有效性取决于密切调节 通过雌激素和肽生长因子促进乳腺细胞生长。然而，在这方面， 随着乳腺癌的进展，这种疾病通常会对 雌激素，大多数患者不再响应治疗， 抗雌激素新的数据显示， 雌激素在癌细胞中被破坏，HER-2扩增 生长因子受体。HER-2过表达发生在25-30%的 绝经后妇女的乳腺癌，并与 临床上内分泌治疗失败。了解生物 这种联系的基础可能有助于改善管理， 提高患者生存率。该项目的具体目标是： 证实HER-2受体过表达在促进 雌激素非依赖性生长，并研究替代治疗 在临床前模型中预防人类乳腺癌进展 绝经后乳腺癌母乳腺癌细胞具有低- HER-2的表达和高表达的生物工程子细胞 HER-2的表达将测试它们对以下的差异敏感性： 雌激素三苯氧胺和纯抗雌激素药此外，我们将评估 抗雌激素治疗联合 下调HER-2受体的抗受体抗体。 2）探讨雌激素受体的调节机制 (ER)通过生长因子受体信号通路。这项研究将 关注HER-2受体的信号转导和潜在的 对野生型和变体ER转录的下游影响， 雌激素受体与雌激素反应元件的结合和相互作用 核，并对ER中酪氨酸和丝氨酸残基的磷酸化 在乳腺癌细胞中。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heregulin的生物学意义，heregulin是一种配体， HER-2/HER-3受体的激活，在乳腺癌进展中 和不依赖雌激素的生长。调蛋白可能是雌激素诱导的 生长因子这一假设将通过测量荷尔蒙来检验。 调蛋白mRNA转录和分泌的调节， heregulIn对绝经后妇女卵巢上皮细胞生长影响的研究 患者抗调蛋白抗体也将被评价为新的 抗肿瘤剂。 这些研究可能会为老年妇女带来新的激素疗法 HER过度表达的乳腺癌