Glucocorticoid receptor-mediated survival signaling in breast cancer

要提高乳腺癌的治愈率，就需要对抗细胞凋亡的分子有详细的了解 癌细胞抵抗化疗和“靶向”治疗的机制。我们的实验室有 发现乳腺癌中一种新的抗凋亡信号通路--糖皮质激素受体 (GR)激活。因为糖皮质激素是生理性应激诱导的激素，而GR是 在乳腺上皮细胞中广泛表达，确定GR介导的潜在机制 上皮细胞存活对于增进我们对癌症病因学和 对治疗的抗拒。目前，人们对GR-R-的下游事件知之甚少。 人乳腺上皮细胞(HMECs)中介导的抗凋亡信号。我们的实验室已经使用了 大规模微阵列和生物信息学分析表征24小时内基因表达的动态变化 HMEC中GR激活后数小时。通过这些研究，我们已经确定了MAP激酶 磷酸酶-1(MKP-1)和血清和糖皮质激素诱导的蛋白激酶-1(SGK-1)作为早期转录 GR的靶点，我们最近证实了GR对SGK-1和MKP-1活性的要求。 传递生存信号。SGK-1和MKP-1，通过它们强大的激酶和磷酸酶活性依次 可调节转录因子ELK-1和FOXOSa的活性。我们假设GR介导的 MKP-1和SGK-1的诱导依次改变ELK-1和FOXOSa的转录活性 导致抗凋亡基因表达的关键变化。在此续期申请中，我们建议继续 这些研究通过确定MKP-1和SGK-1下游诱导的特定机制 有助于细胞存活。在目标1中，GR/MKP-1/ELK-1通路将通过首先验证ELK-1来定义。 1个假定的靶标(从基因表达研究中确定)，然后检查这些靶标在 GR介导的细胞存活。同时，AIM 2将研究GR/SGK-1/FOXOSa途径。此外， 我们将研究这两条通路之间可能存在的分子“串扰”。在《目标3》中，乳腺癌 异种移植模型将被用来确定SGK-1和MKP-1活性在体内抗凋亡中的作用 信号、基因表达和化疗耐药性。这些目标的实现预计将 促进我们对上皮性癌症中的抗凋亡信号和治疗耐药的理解。

Improving breast cancer cure rates will require a detailed molecular understanding of the anti-apoptotic mechanisms used by cancer cells to resist both chemotherapy and "targeted" treatments. Our laboratory has uncovered a novel anti-apoptotic signaling pathway in breast cancer that is initiated glucocorticoid receptor (GR) activation. Because glucocorticoids are physiological stress-induced hormones and the GR is ubiquitously expressed in breast epithelium, identifying the underlying mechanisms of GR-mediated epithelial cell survival has important implications for advancing our knowledge of both cancer etiology and resistance to therapy. Currently, relatively little is known about the downstream events underlying GR- mediated anti-apoptotic signaling in human mammary epithelial cells (hMECs). Our laboratory has used large-scale microarray and bioinformatic analyses to characterize dynamic gene expression changes over 24 hours following GR activation in hMECs. Through these studies, we have identified MAP kinase phosphatase-1 (MKP-1) and serum and glucocorticoid inducible kinase-1 (SGK-1) as early transcriptional targets of the GR, and we have recently demonstrated the requirement for SGK-1 and MKP-1 activity in GR- mediated survival signaling. SGK-1 and MKP-1, via their potent kinase and phosphatase activities, in turn can regulate the activity of the transcription factors ELK-1 and FOXOSa. We hypothesize that GR-mediated induction of MKP-1 and SGK-1 alters ELK-1 and FOXOSa transcriptional activity, respectively, in turn causing key changes in anti-apoptotic gene expression. In this renewal application, we propose to continue these studies by identifying the specific mechanisms downstream of MKP-1 and SGK-1 induction that contribute to cell survival. In Aim 1, the GR/MKP-1/ELK-1 pathway will be defined by first validating the ELK- 1 putative targets (identified from gene expression studies) and then examining the role of these targets in GR-mediated cell survival. In parallel, Aim 2 will examine the GR/SGK-1/ FOXOSa pathway. In addition, the possible molecular "cross-talk" between these two pathways will be investigated. In Aim 3, a breast cancer xenograft model will be used to determine the in vivo role of SGK-1 and MKP-1 activity in anti-apoptotic signaling, gene expression and resistance to chemotherapy. The completion of these aims is expected to advance our understanding of anti-apoptotic signaling and therapy-resistance in epithelial cancers.