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

RASSF1A 作为正常乳腺上皮细胞中雌激素受体 α 的潜在调节因子的特征及其在乳腺癌发生中的意义

• 批准号: 388989224
• 负责人: Professorin Dr. Sonja Thaler
• 金额: --
• 依托单位: European Center for Angioscience (ECAS)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/388989224?language=en
• 关键词: Characterization; RASSF1A; potential; regulator; estrogen

Overexpression of the estrogen receptor alpha (ER alpha) is found in around 70% of all human breast carcinomas, whereas in normal breast tissue ER alpha positive cells are in the minority. Besides regulating proliferation, survival and differentiation of normal breast tissue, the ER alpha plays an important role in breast tumorigenesis. Loss of tumor suppressors that regulate ER alpha expression and function is therefore considered to be one of the most important initial events during breast cancer development. During the previous funding periods, I have shown that RASSF1A inhibits the expression of the ER alpha gene and inhibits ER alpha activity. Furthermore, I have demonstrated that RASSF1A mediates inhibition of ER alpha expression through a complex, hierarchically-organized network that includes the proteins YAP1, Akt, FOXO3A and FOXM1. Additionally, I have demonstrated that RASSF1A efficiently inhibits the ER alpha-mediated outgrowth of breast cancer cells. Furthermore, I have shown that within breast cancer cells RASSF1A not only inhibits ER alpha but also other proteins and signaling pathways that mediate resistance towards ER alpha-inhibitory drugs. Therefore, during the next funding period I plan to investigate whether substances that either imitate the function of RASSF1A or reactivate RASSF1A expression could improve the treatment of ER alpha+ and therapy-resistant breast cancer. To this end I will perform a variety of in vitro and in vivo experiments using primary mammary carcinoma cells from therapy-resistant breast cancer patients. During the previous funding periods, I was also able to demonstrate an inhibitory influence of RASSF1A on the growth of luminal breast tumors using in vivo experiments based on the Rassf1a-/- mouse. These results show that RASSF1A is an important regulator of ER alpha and that the loss of RASSF1A promotes the development of ER alpha+ breast carcinomas. In addition, using the Rassf1a-/- mouse, I have begun to mechanistically investigate the inhibitory effect of RASSF1A on the initiation of breast tumorigenesis. These experiments will be continued and completed during the coming funding period. In addition, I aim to use the Rassf1a-/- mouse to investigate whether the loss of RASSF1A leads to increased inflammatory processes and whether these inflammatory processes have a promoting effect on breast tumorigenesis.

雌激素受体α（ER α）的过表达存在于约70%的所有人类乳腺癌中，而在正常乳腺组织中ER α阳性细胞是少数。除了调节正常乳腺组织的增殖、存活和分化外，ER α在乳腺肿瘤发生中起重要作用。因此，调节ER α表达和功能的肿瘤抑制因子的丧失被认为是乳腺癌发展过程中最重要的初始事件之一。在之前的资助期间，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通过一个复杂的、分层组织的网络介导ER α表达的抑制，该网络包括蛋白质YAP 1、Akt、FOXO 3A和FOXM 1。此外，我已经证明，RASSF 1A有效地抑制ER α介导的乳腺癌细胞的生长。此外，我已经证明，在乳腺癌细胞中，RASSF 1A不仅抑制ER α，还抑制其他蛋白质和信号通路，介导对ER α抑制药物的耐药性。因此，在下一个资助期间，我计划研究模仿RASSF 1A功能或重新激活RASSF 1A表达的物质是否可以改善ER α +和耐药乳腺癌的治疗。为此，我将使用来自治疗抵抗性乳腺癌患者的原代乳腺癌细胞进行各种体外和体内实验。在之前的资助期间，我还能够使用基于Rassf 1a-/-小鼠的体内实验证明RASSF 1A对管腔乳腺肿瘤生长的抑制作用。这些结果表明，RASSF 1A是ER α的重要调节因子，并且RASSF 1A的缺失促进ER α +乳腺癌的发展。此外，使用Rassf 1a-/-小鼠，我已经开始机械地研究RASSF 1A对乳腺肿瘤发生的抑制作用。这些实验将在下一个供资期内继续进行并完成。此外，我的目标是使用Rassf 1a-/-小鼠来研究RASSF 1A的缺失是否会导致炎症过程的增加，以及这些炎症过程是否对乳腺肿瘤的发生有促进作用。