Glucocorticoid receptor-mediated survival signaling in breast cancer

描述(由申请人提供：确定乳腺癌(BC)中驱动治疗抵抗和复发的抗细胞凋亡信号通路对于开发有效的策略以改善侵袭性乳腺癌(BC)患者的预后至关重要。为此，我们确定了糖皮质激素受体(GR)介导的抗细胞凋亡信号在表达GR的人乳腺癌(BC)的体外和体内临床前模型中的重要作用。具体地说，在之前的资助阶段，我们通过在雌激素受体、孕激素受体和HER2阴性BC(三阴性BC或TNBC)模型中识别GR调节的编码激酶(例如SGK1)和磷酸酶(例如MKP1)的基因，确定了GR信号与PI3-K和MAPK通路之间直接相互作用的机制。这一更新建议扩大我们的研究，以实现对糖皮质激素受体(GR)介导的TNBC细胞存活途径的全面了解。我们收集、整理和分析了几个早期BC基因表达研究的数据，并进行了长期的临床随访，并在1300多名患者中检验了原发BC中高GR表达与复发风险之间的关系。我们兴奋地发现，雌激素受体-α(ER)阴性的BCS中GR的高表达确实与早期复发的风险显著增加相关，这支持了我们之前的发现。更有趣的是，我们出人意料地发现，ER阳性、GR过度表达肿瘤的患者复发风险降低。这一令人兴奋的发现开辟了一个新的研究领域：研究BC中GR信号是如何根据ER语境而不同的。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ER+肿瘤中被ER活性特异性拮抗的基因和通路。我们现在建议1)使用GR反式激活的ER拮抗作用作为一种工具来识别其他关键的GR靶基因和途径，2)识别GR反式激活的ER拮抗机制，以及3)在临床前TNBC模型中测试ER拮抗的GR靶基因和途径的功能。这些实验的结果有望通过确定以前未知的GR介导的细胞生存途径来扩大高危ER阴性和TNBC患者的选择范围，这些途径有助于治疗耐药和早期复发。 公共卫生相关性：我们的实验室发现糖皮质激素受体(GR)的表达识别出早期雌激素受体阴性(ER-)和三阴性(ER-/PR-/HER2-)乳腺癌(TNBC)患者的预后非常差。令人惊讶的是，ER阳性肿瘤中GR的表达与相对较好的临床结果相关。我们先前的临床前工作表明，特定靶基因的GR激活可以保护BC细胞免受化疗诱导的细胞凋亡。我们假设ER活性以基因选择性的方式拮抗GR转录功能，从而减少GR靶基因亚集的表达，这些基因可能介导ER乳腺癌的化疗耐药和复发。我们建议使用GR活性的ER拮抗作用作为一种工具来识别预后不良的TNBC的功能相关基因和途径。然后，这些下游的GR通路可以作为TNBC的新治疗靶点进行测试。

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. PUBLIC HEALTH RELEVANCE: Our laboratory has discovered that glucocorticoid receptor (GR) expression identifies a very poor prognosis group of patients with early-stage estrogen receptor-negative (ER-) and triple negative (ER-/PR- /HER2-) breast cancer (TNBC). Surprisingly, GR expression in ER-positive tumors is associated with a relatively good clinical outcome. Our previous pre-clinical work demonstrated that GR activation of specific target genes protects BC cells against chemotherapy-induced apoptosis. We hypothesize that ER activity antagonizes GR transcriptional function in a gene-selective manner, thereby reducing the expression of a subset of GR target genes likely to mediate chemotherapy resistance and relapse in ER- breast cancer. We propose to use ER antagonism of GR activity as a tool for identifying functionally relevant genes and pathways underlying poor prognosis TNBC. These downstream GR pathways can then be tested as novel therapeutic targets in TNBC.