Stoner Matthew, Saville Bradley, Wormke Mark, Dean Dana, Burghardt Robert, Safe Stephen
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843-4466, USA.
Mol Endocrinol. 2002 Oct;16(10):2231-42. doi: 10.1210/me.2001-0347.
Regulation of estrogen receptor alpha (ERalpha) plays an important role in hormone responsiveness and growth of ER-positive breast cancer cells and tumors. ZR-75 breast cancer cells were grown under conditions of normoxia (21% O(2)) or hypoxia (1% O(2) or cobaltous chloride), and hypoxia significantly increased hypoxia-inducible factor 1alpha protein within 3 h after treatment, whereas ERalpha protein levels were dramatically decreased within 6-12 h, and this response was blocked by the proteasome inhibitor MG-132. In contrast, hypoxia induced only minimal decreases in cellular Sp1 protein and did not affect ERalpha mRNA; however, hypoxic conditions decreased basal and 17beta-estradiol-induced pS2 gene expression (mRNA levels) and estrogen response element-dependent reporter gene activity in ZR-75 cells. Although 17beta-estradiol and hypoxia induce proteasome-dependent degradation of ERalpha, their effects on transactivation are different, and this may have implications for clinical treatment of mammary tumors.
雌激素受体α（ERα）的调控在ER阳性乳腺癌细胞和肿瘤的激素反应性及生长过程中起着重要作用。ZR-75乳腺癌细胞在常氧（21% O₂）或低氧（1% O₂或氯化钴）条件下培养，低氧处理后3小时内，低氧诱导因子1α蛋白显著增加，而ERα蛋白水平在6 - 12小时内急剧下降，且这种反应被蛋白酶体抑制剂MG-132阻断。相比之下，低氧仅使细胞Sp1蛋白略有减少，且不影响ERα mRNA；然而，低氧条件下ZR-75细胞中基础和17β-雌二醇诱导的pS2基因表达（mRNA水平）以及雌激素反应元件依赖性报告基因活性均降低。虽然17β-雌二醇和低氧均诱导ERα的蛋白酶体依赖性降解，但其对反式激活的影响不同，这可能对乳腺肿瘤的临床治疗具有重要意义。
