Src, p53 and estrogen receptor-positive breast cancer

Src、p53 和雌激素受体阳性乳腺癌

• 批准号: 8610636
• 负责人: SARA A COURTNEIDGE
• 金额: $ 16.75万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8610636
• 关键词: Adjuvant; Affect; Apoptosis; Autophagocytosis; Behavior; Biological Models; Breast Cancer Cell; Cancer Patient; Cell Cycle; Cell Cycle Progression; Cell Line; Cell Proliferation; Cells; Clinical; Clinical Trials; Dasatinib; Data; Dominant-Negative Mutation; EGF gene; Enrollment; Estrogen Receptors; Estrogen receptor positive; Estrogens; Evaluation; Event; Genomics; Growth Factor; Growth Hormone Receptor; Human; In Vitro; Long-Term Effects; MYC Family Genes; Malignant Neoplasms; Mediating; Mesenchymal; Messenger RNA; MicroRNAs; Mutate; Mutation; Nuclear Receptor Coactivator 3; Oncogenic; Outcome; Outcomes Research; Pathogenesis; Pathway interactions; Patients; Phase II Clinical Trials; Phenotype; Platelet-Derived Growth Factor; Play; Proteins; Publishing; RNA; Research; Role; SU 6656; Signal Pathway; Signal Transduction; Staging; Stimulation of Cell Proliferation; TP53 gene; Tamoxifen; Testing; Transcript; Transcription Factor Oncogene; Trastuzumab; Woman; cancer cell; cancer type; cell growth; cell transformation; disorder control; effective therapy; in vivo; inhibitor/antagonist; innovation; kinase inhibitor; malignant breast neoplasm; meetings; mutant; neoplastic cell; overexpression; public health relevance; research clinical testing; research study; response; small hairpin RNA; src-Family Kinases; success; transcription factor; tumor; tumor progression

Most breast cancers, have increased levels of the tyrosine kinase Src, which has been postulated to promote oncogenic signaling by both growth factor and hormone receptors, as well as to facilitate both survival and invasive behavior. In addition, inhibition of Src has been proposed as a mechanism to restore sensitivity to trastuzumab (in the case of Her2 positive tumors) and tamoxifen (in the case of ER/PR+ tumors). Yet clinical trials in breast cancer with multi-targeted kinase inhibitors that inhibit Src (dasatinib, bosutinib and saracatinib) have yet to meet with great success. For example, a recent phase II trial of dasatinib in progressive advanced breast cancer showed disease control in 19% of patients with ER/PR+ tumors, with no responses noted in Her2+ or triple negative tumors. One notable difference between ER+ and other breast cancers is that p53 mutation is much less common in the former than the latter. It is also known that loss of p53 function leads to a worse outcome in breast cancer. Using mesenchymal cells as a model system, we have previously shown that Src family kinases (SFKs) are required for mitogenesis elicited by a variety of growth factors, including PDGF and EGF. In addition, we have determined that SFKs are required to overcome a cell cycle block controlled by p53: if p53 is absent or mutated, SFKs are no longer necessary for mitogenic signaling. We have confirmed a requirement for SFKs for G1>S progression of breast cancer cells in response to estrogen. We hypothesize that Src is required for tumor cell growth only in those breast cancers with functional p53, and predict that p53 status will dictate how breast cancers will respond to Src inhibitors. The outline of our hypothesis is shown in the schematic. Here we will focus on the effects of ER-activated Src, and for this proposal, not evaluate the genomic and transcription factor crosstalk effects of the estrogen receptor. To test our hypothesis, we will determine the effect of p53 status on the response of ER+ve tumor cells to Src inhibitors, and evaluate the effect of Src inhibition on signaling events downstream of ER. There are several innovative aspects to this proposal, including the first demonstration that p53 status can affect SFK-dependent cell cycle progression of a human cancer cell, and the use of the understudied SFK inhibitor SU11333 both in vitro and in vivo. The outcome of this research will be a more complete understanding of the role of Src in ER+ve breast cancer progression, and how p53 status might affect this. This would set the stage for more in depth analyses of the signaling pathways involved. Furthermore, if our hypothesis is correct, this would have potential clinical impact, and might justify the continued testing of Src inhibitors in ER+ve breast cancer. More broadly, the data might also justify determining p53 status during enrollment in Src inhibitor studies in other cancer types.

大多数乳腺癌都有酪氨酸激酶Src水平的增加，这被认为是促进乳腺癌的发生。 通过生长因子和激素受体的致癌信号传导，以及促进存活和 侵犯性行为此外，Src的抑制已被提出作为恢复对以下的敏感性的机制： 曲妥珠单抗（Her 2阳性肿瘤）和他莫昔芬（ER/PR+肿瘤）。但临床上 使用抑制Src的多靶点激酶抑制剂（达沙替尼、博舒替尼和saracatinib）治疗乳腺癌的试验 尚未取得巨大成功。例如，最近的一项达沙替尼治疗进展性晚期 乳腺癌在19%的ER/PR+肿瘤患者中显示疾病控制， Her 2+或三阴性肿瘤。ER+和其他乳腺癌之间的一个显著差异是p53 突变在前者中比在后者中少得多。还已知p53功能的丧失会导致 乳腺癌的预后更差使用间充质细胞作为模型系统，我们先前已经表明， Src家族激酶（SFKs）是多种生长因子（包括PDGF）诱导的有丝分裂所必需的 EGF此外，我们已经确定，SFKs是克服细胞周期阻滞所必需的， p53：如果p53缺失或突变，SFK不再是促有丝分裂信号传导所必需的。我们已经确认了 乳腺癌细胞对雌激素应答的G1>S进展需要SFKs。我们假设 Src仅在具有功能性p53的乳腺癌中是肿瘤细胞生长所需的，并预测p53 状态将决定乳腺癌将如何响应Src抑制剂。我们的假设的轮廓显示在 示意图在这里，我们将重点关注ER激活的Src的作用，对于这个建议，不评估 雌激素受体的基因组和转录因子串扰效应。为了验证我们的假设，我们将 确定p53状态对ER+ve肿瘤细胞对Src抑制剂的反应的影响，并评估 Src抑制对ER下游信号传导事件的影响。 这项提议有几个创新的方面，包括第一次证明p53状态可以 影响人类癌细胞的SFK依赖性细胞周期进程，以及未充分研究的SFK的使用 抑制剂SU 11333在体外和体内的作用。这项研究的结果将是一个更完整的 了解Src在ER+ve乳腺癌进展中的作用，以及p53状态如何影响这一点。 这将为更深入地分析所涉及的信号通路奠定基础。此外，如果我们 假设是正确的，这将具有潜在的临床影响，并可能证明继续测试Src是合理的 ER+ve乳腺癌中的抑制剂。更广泛地说，这些数据也可能证明在治疗期间确定p53状态是合理的。 在其他癌症类型的Src抑制剂研究中招募。