Characterization of RASSF1A as a potential regulator of the estrogen receptor alpha in normal mammary epithelia and its implication in breast cancer development

ER α的过表达存在于约70%的人类乳腺癌中，而在正常乳腺组织中，ER α +细胞占少数。除了调节正常乳腺组织的增殖、存活和分化外，ER α在乳腺肿瘤的发生中起重要作用。因此，导致ER α表达和功能不足的肿瘤抑制因子的缺失被认为是乳腺癌发展过程中最重要的初始事件之一。在第一个资助期间，我已经证明RASSF 1A抑制ER α基因的表达并抑制ER α活性。此外，我已经证明RASSF 1A介导的ER α表达抑制是Akt依赖性的。在第一步中，RASSF 1A引起Akt的抑制，进而引起FOXO 3A的激活。激活的FOXO 3A可能抑制ER α基因的表达。在第二个资助期间，我将揭示RASSF 1A抑制ER α基因表达的完整机制。因此，我将另外证明RASSF 1A对NF-κ B信号通路的潜在抑制功能及其与ER α基因表达的相关性。在第一个资助期间，我已经开始了基于Rassf 1a-/-小鼠的体内实验。这些实验的目的是研究RASSF 1A对雌激素介导的乳腺癌发生和进展的潜在抑制作用。这些试验应在第二个供资期内完成。此外，我将研究RASSF 1A在孕激素驱动的乳腺癌发生的启动和进展中的潜在抑制功能。此外，我将研究RASSF 1A和小窝蛋白-1是否可能共同抑制ER α的表达和功能，以及对乳腺上皮细胞转化和恶性进展至关重要的信号通路。

Overexpression of ER alpha is found in around 70% of all human breast carcinomas whereas in normal breast tissue, ER alpha+ cells are in the minority. Besides regulating proliferation, survival and differentiation of normal breast tissue, ER alpha plays an important role in the tumorigenesis of breast tumors. Loss of tumor suppressors that lead to inadequate ER alpha expression and function is therefore considered to be one of the most important initial events during breast cancer development. During the first funding period I have shown that RASSF1A inhibits the expression of the ER alpha gene and inhibits ER alpha activity. Furthermore I have demonstrated that the RASSF1A-mediated inhibition of ER alpha expression is Akt dependent. In a first step RASSF1A cause inhibition of Akt and in turn activation of FOXO3A. In the following activated FOXO3A might inhibit ER alpha gene expression. During the second funding period I will reveal the complete mechanism by which RASSF1A inhibits ER alpha gene expression. Therefore I will additionally prove a potential inhibitory function of RASSF1A upon the NF-kB signalling pathway and its relevance for ER alpha gene expression. During the first funding period I have started in vivo experiments based on Rassf1a-/- mice. Aim of these experiments is to investigate a potential inhibitory influence of RASSF1A upon estrogen-mediated breast cancer initiation and progression. These experiments should be finished during the second funding period. Additionally I will investigate a potential inhibitory function of RASSF1A upon initiation and progression of progestin-driven breast cancerogenesis in vivo. Furthermore I will investigate whether RASSF1A and Caveolin-1 might act in concert to inhibit ER alpha expression and function, as well as signalling pathways that are important for breast epithelial cell transformation and malignant progression.