作为转录因子，雌激素受体（ER）是雌激素发挥作用的关键介导者，包括.ERα和ERβ。在乳腺癌发生过程中，具有肿瘤促进作用的ERα表达水平升高，而具有肿瘤抑制作用的ERβ表达水平降低，但调控这一平衡的分子机制至今未明。我们前期的研究表明，雌激素诱导蛋白Pescadillo(PES1)能升高ERα转录活性但降低ERβ转录活性，并且PES1在蛋白水平上升高ERα表达但降低ERβ表达；PES1与ERα和ERβ均存在相互作用。本申请拟在此基础上，进一步确定PES1对ERα和ERβ的转录调节方式及调节的下游靶基因；探索PES1如何通过与ERα和ERβ的相互作用改变ERα和ERβ的蛋白水平；体内外检测PES1对雌激素诱导的乳腺癌细胞生长的影响；利用乳腺癌标本，确定PES1与ERα和ERβ表达的相关性及其临床意义，为阐明乳腺癌发生的分子机制及发现新的乳腺癌诊断和治疗靶标打下坚实基础。

The transcription factor estrogen receptor (ER), inclunding ERα and ERβ, is a key mediator of estrogen. The initiation of breast cancer is associated with increased expression of tumor-promoting ERα and decreased expression of tumor-suppressive ERβ. However, the mechanism underlying this process is unknown. Our previous study showed that Pescadillo/PES1, an estrogen-inducible protein, increased the transcriptional activity of ERα but decreased that of ERβ, with enhanced expression of ERα and reduced expression of ERβ. PES1 interacted with both ERα and ERβ. Based on these observations, we will further investigate the effects of PES1 on ERα and ERβ transactivation and their target gene expression. We will determine how PES1 alters ERα and ERβ expression through its interaction with ERα and ERβ. We will examine the effect of PES1 on estrogen-induced breast cancer cell growth in vitro and in vivo. Using breast cancer specimens, we will define the correlation between PES1 expression and the expression of ERα and ERβ as well as its clinical significance. This study will lay a solid foundation for elucidation of molecular mechanisms of breast tumorigenesis and identification of novel targets of breast cancer diagnosis and therapy.