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.

内分泌治疗通常用于治疗乳腺癌 绝经后妇女，特别是在年龄最大的患者中。 内分泌治疗的功效取决于密切调节 雌激素和肽生长因子的乳腺细胞生长。然而， 随着乳腺癌的进展，该疾病通常变得对 雌激素和大多数患者不再对 抗雌激素。新数据表明，生长调节功能 随着HER-2的扩增，雌激素在癌细胞中被破坏 生长因子受体。 HER-2的过表达发生在25-30％ 绝经后妇女的乳腺癌，与 诊所内分泌治疗失败。了解生物学 该协会的基础可能有助于改善管理和 增加患者的生存。该项目的具体目的是：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治疗 为了预防人类乳腺癌的进展 绝经后乳腺癌。父母乳腺癌细胞低 HER-2和生物工程的女儿细胞的表达高 HER-2的表达将被测试，因为它们的差异敏感性 雌激素，他莫昔芬和纯抗雌激素。此外，我们将评估 抗雌激素治疗的治疗优势与 抗受体抗体，下调HER-2受体。 2）研究调节雌激素受体的机制 （ER）通过生长因子受体信号通路。研究将 专注于HER-2受体和电势转导信号 下游对野生型和变体ER转录的影响 ER与雌激素反应元件的结合和相互作用 核，酪氨酸和丝氨酸残基的磷酸化 在乳腺癌细胞中。反义寡核苷酸至ER mRNA将是 用于定义ER在HER-2促进生长中的可能作用。 3）评估此处糖蛋白的生物学意义，这是一种配体 在乳腺癌进展中激活HER-2/HER-3受体 和雌激素无关的生长。这里可能会导致雌激素诱导 增长因素。该假设将通过荷尔蒙测量来检验 这里调节糖蛋白mRNA转录和分泌以及通过 研究结肠蛋白对绝经后细胞生长的影响 患者。抗甲状腺素抗体也将被评估为新颖 抗肿瘤剂。 这些研究可能导致老年妇女的新激素疗法 与她过表达的乳腺癌。