MUTATIONS IN INDIVIDUAL BREAST CANCERS--PCR SEQUENCING

个体乳腺癌的突变——PCR 测序

基本信息

批准号：
2094702
负责人：
Suzanne AW Fuqua
金额：
$ 7.2万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-03-01 至 1995-02-28
项目状态：
已结题

项目摘要

Breast cancer is one of the few human malignancies to endocrine manipulation, with the presence of estrogen receptor (ER) in breast tumors identifying a group of patients most likely to respond to endocrine therapy. Unfortunately, though about 60% of breast cancer patients are positive for ER expression, only about 30% respond significantly to endocrine therapy. Additionally, some breast tumors initially estrogen- responsive eventually become resistant to endocrine therapy. Therefore, defining the factors which affect ER expression and function are crucial to understand breast cancer behavior and how to choose effective treatment. Because structural polymorphisms or mutations within domains can directly affect expression and protein function, we here propose to examine the ER sequences for structural alterations of functional significance. With the new technique termed polymerase chain reaction, PCR, it is now possible to rapidly clone and sequence genes. We will address the feasibility of using the PCR amplification technique to amplify, clone, and sequence ER sequences from clinical breast tumor specimens. We will focus on three situations in which there is a discordance between ER and the estrogen- induced progesterone receptor (PR), or between ER and hormone response of the tumor. Using the PCR technique to examine selected portions of the ER sequence, we will ask: 1) whether there are mutations in the ER hormone binding domain sometimes responsible for the ER-PR+ phenotype; 2) whether there are mutations in the ER DNA binding domain sometimes responsible for ER+ PR-phenotype; and 3) whether there are mutations in either domain sometimes responsible for the failure of hormone therapy in ER+ breast cancer. Finally, we will ask: 4) whether in a larger series of clinical breast cancer specimens, these mutations correlate with ER expression and with recurrence and survival. These analyses will give valuable insight into the molecular defects or polymorphisms which impact on either ER expression or hormone- responsiveness during therapy. Therefore, the proposed work could directly affect treatment strategies for breast cancer.

乳腺癌是少数影响内分泌的人类恶性肿瘤之一乳腺肿瘤中存在雌激素受体（ER）确定一组最有可能对内分泌产生反应的患者治疗。不幸的是，尽管大约 60% 的乳腺癌患者 ER 表达呈阳性，只有约 30% 的人对内分泌治疗。此外，一些乳腺肿瘤最初会产生雌激素- 反应性最终会对内分泌治疗产生耐药性。所以，确定影响 ER 表达和功能的因素至关重要了解乳腺癌的行为以及如何选择有效的治疗。因为结构域内的结构多态性或突变可以直接影响表达和蛋白质功能，我们在这里建议检查 ER 具有功能意义的结构改变的序列。随着称为聚合酶链式反应（PCR）的新技术，现在可以快速克隆和测序基因。我们将探讨可行性使用 PCR 扩增技术对 ER 进行扩增、克隆和测序临床乳腺肿瘤标本的序列。我们将重点关注三个方面 ER 和雌激素之间存在不一致的情况诱导孕激素受体 (PR)，或 ER 和激素反应之间肿瘤。使用 PCR 技术检查 ER 的选定部分序列，我们会问：1）ER激素是否有突变结合域有时负责 ER-PR+ 表型； 2）是否 ER DNA 结合域中存在突变，有时会导致 ER+ PR-表型； 3）任一结构域是否存在突变有时是 ER+ 乳房激素治疗失败的原因癌症。最后，我们会问：4）是否在更大系列的临床中在乳腺癌样本中，这些突变与 ER 表达相关具有复发性和生存率。这些分析将为分子缺陷或分子缺陷提供有价值的见解。影响 ER 表达或激素的多态性治疗期间的反应性。因此，拟议的工作可以直接影响乳腺癌的治疗策略。