Glucocorticoid receptor-mediated survival signaling in breast cancer

提高乳腺癌的治愈率需要对抗凋亡基因进行详细的分子理解。 癌细胞抵抗化疗和“靶向”治疗的机制。本实验室 揭示了乳腺癌中一种新的抗凋亡信号通路， (GR)activation.因为糖皮质激素是生理应激诱导的激素，而GR是 普遍表达于乳腺上皮细胞，确定GR介导的乳腺癌的潜在机制。 上皮细胞存活对于提高我们对癌症病因学和 对治疗的抵抗目前，对GR的下游事件知之甚少， 在人乳腺上皮细胞（hMEC）中介导的抗凋亡信号传导。我们的实验室使用了 大规模微阵列和生物信息学分析，以表征超过24 在hMEC中GR激活后24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激酶-1（SGK-1）作为早期转录因子， GR的靶点，我们最近已经证明了GR中对SGK-1和MKP-1活性的要求， 介导的生存信号。SGK-1和MKP-1通过其强有力的激酶和磷酸酶活性，依次 可以调节转录因子ELK-1和FOXOSa的活性。我们假设GR介导的 MKP-1和SGK-1诱导分别改变ELK-1和FOXOSa转录活性 引起抗凋亡基因表达的关键变化。在这一更新申请中，我们建议继续 这些研究通过确定MKP-1和SGK-1诱导下游的特定机制， 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个假定的靶点（从基因表达研究中鉴定），然后检查这些靶点在 GR介导的细胞存活。同时，目标2将检查GR/SGK-1/ FOXOSa通路。此外该 将研究这两种途径之间可能的分子“串扰”。在目标3中，乳腺癌 异种移植模型将用于确定SGK-1和MKP-1活性在抗细胞凋亡中的体内作用。 信号传导、基因表达和对化疗的抗性。这些目标的完成预计将 促进我们对上皮癌中抗凋亡信号传导和治疗抗性的理解。

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.