G protein-coupled estrogen receptor GPER and breast carcinogenesis

选择性雌激素受体（ER）调节剂和下调剂（SERM和SERD， 被称为抗激素）挽救了数百万ER阳性乳腺癌妇女的生命 癌不幸的是，这些妇女中约有三分之一表现出内在的抵抗力， 这些有针对性的治疗，而类似比例的妇女与抗激素治疗将发展 随着时间的推移，耐药性，导致复发的往往更积极的癌症。SERMs和 SERD抑制经典的核雌激素受体ERα，导致细胞增殖抑制， 增殖和生存。相反，我们的研究结果表明，这些相同的药物激活了 7-跨膜G蛋白偶联雌激素受体GPER，导致 刺激促存活PI 3 K/Akt轴。此外，我们最近的研究表明， 这可能通过FOXO 3促凋亡转录的磷酸化和失活而发生 因子我们已经确定了一系列新的化合物，它们对以下两种化合物都表现出很强的选择性： ERα或GPER。通过将这些药理学方法与遗传学方法相结合，我们 假设对抗激素的获得性抗性涉及GPER的激活， 在FOXO 3的失活中。我们建议以下列具体目标来检验这一假设： 目的1将测试GPER是否介导获得性乳腺癌对SERM和SERD的耐药性。 目的2将测试FOXO 3的失活是否代表增强肿瘤细胞增殖的关键步骤。 面对ERα抑制的生存。目的3将采用自发性乳腺癌的小鼠模型 癌症，以测试是否阻断GPER活性与他莫昔芬治疗组合，或 或者用新药选择性抑制ERα，防止获得性耐药。 意义：这些目标的实现将大大提高我们对联合国作用的认识。 新型雌激素受体GPER在乳腺癌获得性抗激素抵抗中的作用识别 GPER作为乳腺癌获得性抗激素抵抗的新介质 在该提议中使用待评估的新型高选择性配体可导致显著的 150，000名被诊断为ER阳性乳腺癌的妇女， 年

Selective estrogen receptor (ER) modulators and downregulators (SERMs and SERDs, also refereed to as anti-hormones) have saved the lives of millions of women with ER-positive breast cancer. Unfortunately, approximately one-third of these women display intrinsic resistance to these targeted therapies, while a similar fraction of women treated with anti-hormones will develop resistance over time, resulting in recurrences of often more aggressive cancers. SERMs and SERDs inhibit the classical nuclear estrogen receptor ERα, leading to the inhibition of cell proliferation and survival. In contrast, our results have shown that these same drugs activate the 7-transmembrane spanning G protein-coupled estrogen receptor GPER, resulting in the stimulation of the pro-survival PI3K/Akt axis. Furthermore, our recent studies have suggested that this may occur through phosphorylation and inactivation of the FOXO3 pro-apoptotic transcription factor. We have identified a collection of novel compounds that display strong selectivity for either ERα or GPER. By combining these pharmacological approaches with genetic approaches, we hypothesize that acquired resistance to anti-hormones involves their activation of GPER, resulting in the inactivation of FOXO3. We propose to test this hypothesis with the following specific aims: Aim 1 will test whether GPER mediates acquired breast cancer resistance to SERMs and SERDs. Aim 2 will test whether the inactivation of FOXO3 represents a critical step in enhancing tumor cell survival in the face of ERα inhibition. Aim 3 will employ a murine model of spontaneous breast cancer to test whether blocking GPER activity in combination with tamoxifen treatment, or alternatively selectively inhibiting ERα with novel drugs, prevents acquired resistance. Significance: Completion of these aims will significantly advance our knowledge of the role of the novel estrogen receptor GPER in acquired anti-hormone resistance in breast cancer. Identifying GPER as a novel mediator in acquired anti-hormone resistance in breast cancer in combination with the use novel highly selective ligands to be evaluated in this proposal could lead to significant improvements in outcome for the150,000 women diagnosed with ER-positive breast cancer each year.