Boerner Julie L, Gibson Matthew A, Fox Emily M, Posner Erika D, Parsons Sarah J, Silva Corinne M, Shupnik Margaret A
Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908, USA.
Mol Endocrinol. 2005 Nov;19(11):2660-70. doi: 10.1210/me.2004-0439. Epub 2005 Jun 23.
Breast cancer cell growth may be stimulated by 17beta-estradiol (E2) or growth factors like epidermal growth factor (EGF). However, tumors typically depend on only one of these pathways and may overexpress either estrogen receptor (ER) or EGF receptor (EGFR) and related family members. Tumors overexpressing EGFR are more aggressive than those expressing ER. Intracellular mediators of these growth-stimulatory pathways are not completely defined, but one potential common mediator of EGF and E2 signaling is the transcription factor signal transducer and activator of transcription 5 (STAT5). To investigate the role of STAT5 in potential crosstalk between E2 and EGF, MDA-MB231 and SKBr3 breast cancer cells, which are ER-negative and overexpress human EGF family receptors, were used. Introduction of ERalpha and treatment with E2 decreased EGF-induced tyrosine phosphorylation of STAT5b, basal and EGF-induced STAT5-mediated transcription, and EGF-stimulated DNA synthesis in these cells. Suppressive effects of E2-EpsilonRalpha were specific for STAT5, as EGF stimulation of MAPK was unaffected. Deletion/mutation analysis of ERalpha demonstrated that the DNA-binding domain was insufficient, and that the ligand-binding domain was required for these responses. ERalpha transcriptional activity was not necessary for suppression of STAT5 activity. Overexpression of c-Src did not prevent suppression of STAT5 activity by E2 and ERalpha. However, ERalpha did prevent basal increases in STAT5 activity with overexpressed c-Src. In the context of human EGF receptor family overexpression, E2-ER opposes EGF signaling by regulating STAT5 activity. STAT5 may be a crucial point of signaling for both E2 and growth factors in breast cancer cells, allowing targeted therapy for many types of breast tumors.
17β-雌二醇（E2）或表皮生长因子（EGF）等生长因子可刺激乳腺癌细胞生长。然而，肿瘤通常仅依赖于这些途径中的一种，可能会过度表达雌激素受体（ER）或表皮生长因子受体（EGFR）及相关家族成员。过度表达EGFR的肿瘤比表达ER的肿瘤更具侵袭性。这些生长刺激途径的细胞内介质尚未完全明确，但EGF和E2信号传导的一个潜在共同介质是转录因子信号转导和转录激活因子5（STAT5）。为了研究STAT5在E2和EGF之间潜在串扰中的作用，使用了ER阴性且过度表达人EGF家族受体的MDA-MB231和SKBr3乳腺癌细胞。引入ERα并用E2处理可降低EGF诱导的STAT5b酪氨酸磷酸化、基础及EGF诱导的STAT5介导的转录，以及这些细胞中EGF刺激的DNA合成。E2-ERα的抑制作用对STAT5具有特异性，因为EGF对MAPK的刺激不受影响。对ERα的缺失/突变分析表明，DNA结合结构域不足，而这些反应需要配体结合结构域。ERα转录活性对STAT5活性的抑制不是必需的。c-Src的过表达并不能阻止E2和ERα对STAT5活性的抑制。然而，ERα确实阻止了过表达c-Src时STAT5活性的基础增加。在人EGF受体家族过度表达的情况下，E2-ER通过调节STAT5活性来对抗EGF信号传导。STAT5可能是乳腺癌细胞中E2和生长因子信号传导的关键节点，从而为多种类型的乳腺肿瘤提供靶向治疗。
