GPR30/EGFR"串话"促进三阴性乳腺癌（TNBC）上皮间质化（EMT）的分子机制

Triple negative breast cancer (TNBC) is characterized by estrogen receptor (ER) negative, progesterone receptor (PgR) negative and human epidermal growth factor receptor 2 (HER-2) negative, its tumor malignant degree is significantly correlated with the epithelial to mesenchymal transitions (EMT). These patients do not benefit from endocrine therapy and show a poorer prognosis than patients with ER-positive tumor because endocrine and targeted therapy has no significant clinical effect. Due to its high malignancy, rapid growth and poor prognosis, it is an urgent need to explore new drug targets and therapy method. Our recent studies revealed that GPR30 can promote the EMT of TNBC and then trigger its proliferation and metastasis; therefore it can be a potential treatment target for TNBC. Considering that the activities of GPR30 are mediated by the cross-take of GPR30 and EGFR, the present proposal will study the mechanisms of GPR30/EGFR cross talk and then trigger the EMT of TNBC to evaluate the poor therapeutic effects of EGFR-targeted treatment, and then evaluate the feasibility to treatment TNBC on the basis of targeted GPR30/EGFR cross talk. Our study will break our cognitive limitation that there is no drug target for TNBC treatment and afford new approach to therapy TNBC.

三阴性乳腺癌(TNBC)是指雌激素受体(ER)、孕激素受体(PR)和人表皮生长因子受体2 (HER2)均为阴性的乳腺癌，约占全部乳腺癌的15～20％。由于无法实行靶向治疗，TNBC与其它乳腺癌相比预后最差。开发出TNBC的治疗靶点已成为乳腺癌领域亟待解决的关键问题。我们前期研究表明膜雌激素受体GPR30能促进TNBC发生上皮间质转化（EMT），从而促进TNBC发生发展。鉴于GPR30的功能受GPR30与EGFR之间的"串话"（cross-talk）机制调控，我们拟以GPR30/EGFR的"串话"为靶点研究其在促进TNBC发生EMT过程中的作用及其分子机制，解释临床上单独以EGFR为TNBC治疗靶点难以取得满意疗效的原因，并探讨以GPR30/EGFR"串话"为靶点治疗TNBC的可行性。以期突破以往认为TNBC无法实行靶向治疗的传统观念，为TNBC的临床治疗提供新的具有重大潜力的作用靶点。

三阴性乳腺癌(TNBC)是指雌激素受体(ER)、孕激素受体(PR)和人表皮生长因子受体2 (HER2)均为阴性的乳腺癌，约占全部乳腺癌的15～20％。由于无法实行靶向治疗，TNBC与其它乳腺癌相比预后最差。开发出TNBC的治疗靶点已成为乳腺癌领域亟待解决的关键问题。G蛋白偶联受体30（G-protein coupled receptor 30，GPR30）是七次跨膜的G蛋白偶联受体，可介导雌激素的快速非基因型反应。然而其在ER阴性乳腺癌发生发展中的作用目前尚知之甚少。我们的研究发现GPR30受体特异性激活剂G-1可以引起细胞周期G2/M期阻滞并诱导p53依赖性的细胞凋亡，同时可以抑制NF-κB的活性降低乳腺癌细胞侵袭转移能力。此外，GPR30活化后可抑制白介素6（IL-6）的生成从而抑制TNBC血管形成能力。裸鼠移植瘤模型实验证实G-1可有效抑制乳腺癌的生长和转移，提高裸鼠的生存期。临床TNBC患者样本统计分析表明GPR30的表达与淋巴结转移、组织学分级呈显著（p<0.01）负相关，而与临床预后性呈显著（p<0.01）正相关。以上结果表明GPR30受体活化后可显著抑制ER阴性乳腺癌的进程，其特异性激动剂G-1具备作为ER阴性乳腺癌候选药物的潜质。