MAPKs Regulate Progesterone Receptors by SUMO Modulation

描述（由申请人提供）：乳腺癌通常具有增加的丝裂原活化蛋白激酶（MARK）活性，并且该途径部分地通过靶向类固醇激素受体来影响乳腺癌细胞生长。输入MAPK的信号分子的过表达赋予他莫昔芬抗性。雌激素受体-α（ER）和孕激素受体（PR）是正常乳腺发育所必需的，也是大多数乳腺癌发生和发展所必需的。这些受体独立发挥作用，但也明显相互作用，以调节激素的反应。例如，PR可以通过调节PR N-末端表现出自抑制，以及通过抑制ER的转录活性表现出反式阻遏。通过SUMO-1的共价连接（类小泛素化）对PR N-末端的翻译后修饰是PR自身抑制和ER的反式阻遏所需的。PR N-末端也被多种蛋白激酶严重磷酸化。磷酸化的PR-B是sumoylated不足，从而预测PR和ER活性的去抑制和对雌激素的反应性增加。我们假设PR N-末端的过度磷酸化导致PR类小泛素化的丧失以及表达功能性受体但对基于类固醇激素的疗法有抗性的晚期乳腺癌中PR和ER功能的调节改变。因此，生长因子可能通过PR的直接磷酸化而篡夺类固醇激素对乳腺癌细胞生长的控制，进而改变PR类小泛素化和关键的PR/ER相互作用，从而影响肿瘤对抗雌激素的反应。我们将使用体外和体内方法来测试我们的新假设。研究的问题包括：1）生长因子和/或类固醇激素是否以磷酸化依赖的方式差异调节PR类小泛素化？2)生长因子和/或类固醇激素是否以SUMO依赖性方式调节ER和PR活性？和3）PR的类小泛素化能否改变雌激素依赖性乳腺癌细胞生长和/或逆转体内他莫昔芬耐药肿瘤的敏感性？了解生长因子控制类固醇激素功能的机制将允许开发乳腺癌治疗的新途径。

DESCRIPTION (provided by applicant): Breast cancers often have increased mitogen-activated protein kinase (MARK) activity, and this pathway influences breast cancer cell growth in part by targeting steroid hormone receptors. Overexpression of signaling molecules that input to MAPKs confer tamoxifen resistance. Estrogen receptor-alpha (ER) and progesterone receptors (PR) are required for normal breast development and essential for the development and progression of the majority of breast cancers. These receptors function independently, but also clearly interact to regulate hormone responsiveness. For example, PR can exhibit autoinhibition via regulation of the PR N-terminus, and transrepression by suppression of the transcriptional activities of ER. Post- translational modification of the PR N-terminus by covalent attachment of SUMO-1 (sumoylation) is required for both PR autoinhibition and transrepression of ER. The PR N-terminus is also heavily phosphorylated by multiple protein kinases. Phosphorylated PR-B are under-sumoylated, thus predicting the derepression of PR and ER activities and increased responsiveness to estrogens. We hypothesize that hyper- phosphorylation of the PR N-terminus leads to loss of PR sumoylation and altered regulation of PR and ER function in advanced breast cancers that express functional receptors, yet are resistant to steroid hormone- based therapies. Thus, growth factors may usurp steroid hormone control of breast cancer cell growth by direct phosphorylation of PR, in turn altering PR sumoylation and critical PR/ER interactions, thereby influencing the tumor response to anti-estrogens. We will test our novel hypothesis using both in vitro and in vivo approaches. Questions for study include; 1) Do growth factors and/or steroid hormones differentially regulate PR sumoylation in a phosphorylation-dependent manner? 2) Do growth factors and/or steroid hormones modulate ER and PR activities in a SUMO-dependent manner? and 3) Can sumoylation of PR alter estrogen-dependent breast cancer cell growth and/or reverse the sensitivity of tamoxifen-resistant tumors in vivo? Understanding the mechanisms of growth factor control of steroid hormone function will allow the exploitation of novel pathways for breast cancer treatment.