Cancer Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital Clinical School and Bioanalytical Mass Spectrometry Facility, University of New South Wales, Sydney, New South Wales, Australia.
Cancer Res. 2010 Nov 15;70(22):9391-401. doi: 10.1158/0008-5472.CAN-10-0911. Epub 2010 Sep 21.
To identify therapeutic targets and prognostic markers for basal breast cancers, breast cancer cell lines were subjected to mass spectrometry-based profiling of protein tyrosine phosphorylation events. This revealed that luminal and basal breast cancer cells exhibit distinct tyrosine phosphorylation signatures that depend on pathway activation as well as protein expression. Basal breast cancer cells are characterized by elevated tyrosine phosphorylation of Met, Lyn, EphA2, epidermal growth factor receptor (EGFR), and FAK, and Src family kinase (SFK) substrates such as p130Cas. SFKs exert a prominent role in these cells, phosphorylating key regulators of adhesion and migration and promoting tyrosine phosphorylation of the receptor tyrosine kinases EGFR and Met. Consistent with these observations, SFK inhibition attenuated cellular proliferation, survival, and motility. Basal breast cancer cell lines exhibited differential responsiveness to small molecule inhibitors of EGFR and Met that correlated with the degree of target phosphorylation, and reflecting kinase coactivation, inhibiting two types of activated network kinase (e.g., EGFR and SFKs) was more effective than single agent approaches. FAK signaling enhanced both proliferation and invasion, and Lyn was identified as a proinvasive component of the network that is associated with a basal phenotype and poor prognosis in patients with breast cancer. These studies highlight multiple kinases and substrates for further evaluation as therapeutic targets and biomarkers. However, they also indicate that patient stratification based on expression/activation of drug targets, coupled with use of multi-kinase inhibitors or combination therapies, may be required for effective treatment of this breast cancer subgroup.
为了鉴定基底型乳腺癌的治疗靶点和预后标志物，我们对乳腺癌细胞系进行了基于质谱的酪氨酸磷酸化事件谱分析。结果表明，腔面型和基底型乳腺癌细胞表现出不同的酪氨酸磷酸化特征，这些特征取决于通路激活和蛋白表达。基底型乳腺癌细胞的特征是 Met、Lyn、EphA2、表皮生长因子受体 (EGFR) 和 FAK 的酪氨酸磷酸化水平升高，以及 Src 家族激酶 (SFK) 底物如 p130Cas 的酪氨酸磷酸化水平升高。SFK 在这些细胞中发挥着重要作用，磷酸化黏附和迁移的关键调节因子，并促进受体酪氨酸激酶 EGFR 和 Met 的酪氨酸磷酸化。与这些观察结果一致，SFK 抑制可减弱细胞增殖、存活和迁移。基底型乳腺癌细胞系对 EGFR 和 Met 的小分子抑制剂表现出不同的反应性，这与靶标磷酸化程度相关，反映了激酶共激活，抑制两种类型的激活型网络激酶（例如 EGFR 和 SFK）比单一药物方法更有效。FAK 信号增强了增殖和侵袭，Lyn 被鉴定为与基底表型和乳腺癌患者预后不良相关的网络中的侵袭性成分。这些研究强调了多种激酶和底物，可进一步评估作为治疗靶点和生物标志物。然而，它们也表明，基于药物靶点的表达/激活对患者进行分层，结合使用多激酶抑制剂或联合疗法，可能是治疗这种乳腺癌亚组的有效方法。
