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制定改善侵袭性乳腺癌（BC）患者预后的有效策略至关重要。为此，我们已经确定了糖皮质激素受体（GR）介导的抗凋亡信号在体外和体内表达GR的人乳腺癌（BC）临床前模型中的重要作用。具体而言，在之前的资助期内，我们通过鉴定GR调节的基因编码激酶（如SGK1）和磷酸酶（如MKP1），在雌激素受体、孕激素受体和her2阴性BC（三阴性BC或TNBC）模型中GR介导的细胞存活所必需的GR信号传导与PI3-K和MAPK途径之间的直接串导机制。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、整理和分析了一些早期BC基因表达研究的数据，并进行了长期临床随访，并在1300多例患者中检查了原发性BC中高GR表达与复发风险之间的关系。我们很高兴地发现，雌激素受体- α (ER)阴性的bc中高GR表达确实与早期复发的风险显著增加有关，这支持了我们之前的发现。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中如何根据ER环境而不同。我们假设，在ER阴性的BC（包括TNBC）中，gr介导的基因表达激活了在ER阳性肿瘤中被ER活性特异性拮抗的基因和途径。我们现在提出：1)利用GR转激活的内质网拮抗性作为工具来识别其他关键GR靶基因和治疗耐药TNBC的通路；2)确定GR转激活的内质网拮抗性的机制；3)在临床前TNBC模型中测试内质网拮抗性GR靶基因和通路的功能。这些实验的结果有望通过确定以前未知的gr介导的细胞存活途径来扩大高风险er阴性和TNBC患者的选择，这些途径有助于治疗耐药和早期复发。

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.