Glucocorticoid receptor-mediated survival signaling in breast cancer

描述（由申请人提供：确定驱动乳腺癌（BC）治疗耐药和复发的抗凋亡信号通路对于开发改善侵袭性乳腺癌（BC）患者结局的有效策略至关重要。为此，我们已经鉴定了糖皮质激素受体（GR）介导的抗凋亡信号传导在表达GR的人乳腺癌（BC）的体外和体内临床前模型中的重要作用。具体而言，在上一个资助期，我们通过鉴定雌激素受体、孕酮受体和HER 2阴性BC（三阴性BC或TNBC）模型中GR介导的细胞存活所需的GR调节基因编码激酶（如SGK 1）和磷酸酶（如MKP 1），确定了GR信号传导与PI 3-K和MAPK通路之间直接串扰的潜在机制。这一更新建议扩大我们的研究，以全面了解TNBC中糖皮质激素受体（GR）介导的细胞存活途径。我们收集、整理和分析了几项早期BC基因表达研究的数据，并进行了长期临床随访，并在1300多名患者中研究了原发性BC中GR高表达与复发风险之间的相关性。我们很高兴地发现，雌激素受体α（ER）阴性的乳腺癌中GR的高表达确实与早期复发的风险显著增加有关，支持了我们以前的发现。更有趣的是，我们意外地发现ER阳性、GR过表达肿瘤患者的复发风险降低。这一令人兴奋的发现开辟了一个新的研究领域：研究GR信号在BC中的差异如何取决于ER背景。我们假设ER阴性BC（包括TNBC）中GR介导的基因表达激活了ER+肿瘤中ER活性特异性拮抗的基因和途径。我们现在提出1）使用GR反式激活的ER拮抗作用作为工具来鉴定额外的关键GR靶基因和治疗抗性TNBC的潜在途径，2）鉴定GR反式激活的ER拮抗作用的潜在机制，和3）测试临床前TNBC模型中ER拮抗的GR靶基因和途径的功能。这些实验的结果预计将通过确定以前未知的GR介导的细胞存活途径，为高风险ER阴性和TNBC患者提供更多选择，这些细胞存活途径有助于治疗耐药性和早期复发。

DESCRIPTION (provided by applicant: Identifying anti-apoptotic signaling pathways driving therapy resistance and relapse in breast cancer (BC) is essential for developing effective strategies for improving outcome in patients with aggressive breast cancer (BC). To this end, we have identified an important role for glucocorticoid receptor (GR)-mediated anti- apoptotic signaling in both in vitro and in vivo pre-clinical models of GR-expressing human breast cancer (BC). Specifically, in the previous funding period we identified mechanisms underlying direct cross-talk between GR signaling and the PI3-K and MAPK pathways through identifying GR-regulated genes encoding kinases (e.g. SGK1) and phosphatases (e.g. MKP1) required for GR-mediated cell survival in estrogen receptor, progesterone receptor and HER2-negative BC (triple-negative BC or TNBC) models. This renewal proposes to expand our studies to achieve a comprehensive understanding of pathways mediated by glucocorticoid receptor (GR)-mediated cell survival in TNBC. We have collected, curated, and analyzed data from several early BC gene expression studies with long-term clinical follow-up and examined the association between high GR expression in primary BCs and risk of relapse in over 1300 patients. We were excited to find that high GR expression in estrogen receptor-alpha (ER)-negative BCs indeed associates with a significantly increased risk of early relapse, supporting our previous discoveries. More interestingly, we unexpectedly found that risk of relapse was reduced in patients with ER-positive, GR over expressing tumors. This exciting finding opens up a new area of study: Investigating how GR-signaling differs in BC depending upon ER context. We hypothesize that GR-mediated gene expression in ER-negative BC (including TNBC) activates genes and pathways that are specifically antagonized by ER activity in ER+ tumors. We now propose to 1) use ER antagonism of GR transactivation as a tool to identify additional critical GR target genes and pathways underlying therapy- resistant TNBC, 2) to identify mechanisms underlying ER antagonism of GR transactivation, and 3) to test the function of ER-antagonized GR target genes and pathways in preclinical TNBC models. The results of these experiments are expected to expand options for high-risk ER-negative and TNBC patients by identifying previously unknown GR-mediated cell survival pathways contributing to therapy resistance and early relapse.