Src, p53 and estrogen receptor-positive breast cancer

大多数乳腺癌都有酪氨酸激酶Src水平的升高，这被认为是促进 通过生长因子和激素受体的致癌信号，以及促进生存和 侵犯性行为。此外，对Src的抑制也被认为是恢复对 曲妥珠单抗(在Her2阳性的肿瘤中)和他莫昔芬(在ER/PR+的肿瘤中)。然而，临床上 多靶点抑制src的激酶抑制剂(达沙替尼、波苏替尼和沙拉卡替尼)治疗乳腺癌的试验 还没有取得巨大的成功。例如，最近达沙替尼在进展期晚期的II期试验 在ER/PR阳性的肿瘤患者中，19%的乳腺癌患者表现出疾病控制，没有记录到有反应 HER2+或三重阴性肿瘤。ER+与其他乳腺癌的一个显著区别是P53 前者的突变要比后者少得多。我们还知道，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，我们之前已经证明 SRC家族激酶(Sfk)是包括PDGF在内的多种生长因子诱导的有丝分裂过程所必需的。 和EGF。此外，我们已经确定SFK是克服由以下因素控制的细胞周期阻滞所必需的 P53：如果P53缺失或突变，SFK就不再是有丝分裂信号所必需的。我们已经确认了一项 雌激素对乳腺癌细胞G1、GT；S进展的要求。我们假设 只有在那些具有功能性P53的乳腺癌中，肿瘤细胞生长才需要Src，并预测P53 状态将决定乳腺癌对Src抑制剂的反应。我们假设的概要如图所示 原理图。在这里，我们将重点关注ER激活的Src的影响，对于此提案，不评估 雌激素受体的基因组和转录因子串扰效应。为了检验我们的假设，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，并评价 Src抑制对内质网下游信号事件的影响。 这项提案有几个创新方面，包括第一次证明了P53基因的状态可以 影响依赖SFK的人类癌细胞的细胞周期进程，以及未被研究的SFK的使用 体外和体内的抑制剂SU11333。这项研究的结果将是更加完整的 了解Src在ER+VE乳腺癌进展中的作用，以及P53状态如何影响这一过程。 这将为更深入地分析所涉及的信号通路奠定基础。此外，如果我们的 假设是正确的，这将具有潜在的临床影响，并可能证明继续进行Src测试是合理的。 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 参加其他癌症类型的Src抑制剂研究。

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.