Src, p53 and estrogen receptor-positive breast cancer

描述（由申请人提供）：大多数乳腺癌都有酪氨酸激酶Src水平升高，这被认为可以促进生长因子和激素受体的致癌信号传导，并促进生存和侵袭行为。此外，抑制Src被认为是恢复对曲妥珠单抗（Her2阳性肿瘤）和他莫昔芬（ER/PR+肿瘤）敏感性的一种机制。然而，在乳腺癌中使用抑制Sr的多靶点激酶抑制剂（达沙替尼、博舒替尼和萨拉卡替尼）的临床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的II期试验显示，19%的ER/PR+肿瘤患者疾病得到控制，而Her2+或三阴性肿瘤患者没有反应。ER+和其他乳腺癌的一个显著区别是，前者的p53突变比后者少得多。我们还知道，p53功能的丧失会导致乳腺癌更糟糕的结果。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（SFKs）是多种生长因子（包括PDGF和EGF）诱导的有丝分裂所必需的。此外，我们已经确定sfk是克服由p53控制的细胞周期阻滞所必需的：如果p53缺失或突变，sfk不再是有丝分裂信号传导所必需的。我们已经证实SFKs在乳腺癌细胞对雌激素的反应中G1 bb0 S进展中是必需的。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的状态将决定乳腺癌对Src抑制剂的反应。我们的假设的轮廓如图所示。在这里，我们将重点关注er激活Src的作用，对于本提案，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抑制剂反应的影响，并评估Src抑制对ER下游信号事件的影响。这一提议有几个创新之处，包括首次证明p53状态可以影响人类癌细胞的SFK依赖性细胞周期进展，以及在体外和体内使用未充分研究的SFK抑制剂SU11333。这项研究的结果将是更全面地了解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。这将为对所涉及的信号通路进行更深入的分析奠定基础。此外，如果我们的假设是正确的，这将有潜在的临床影响，并可能证明在ER+ve乳腺癌中继续测试Src抑制剂是合理的。更广泛地说，这些数据也可能证明在其他癌症类型的Src抑制剂研究入组期间确定p53状态是合理的。

DESCRIPTION (provided by applicant): 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 Sr (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.