Prince Henry's Institute, Block E Level 4, Monash Medical Centre, 246 Clayton Road, Clayton, Melbourne, Victoria 3168, Australia.
J Steroid Biochem Mol Biol. 2011 Nov;127(3-5):439-43. doi: 10.1016/j.jsbmb.2011.06.005. Epub 2011 Jun 12.
The liver kinase B1 (LKB1) is encoded by the STK11 gene and acts as a tumour suppressor and a regulator of energy homeostasis. LKB1 expression is reduced in primary breast tumours compared to normal breast epithelium. Although its expression in primary tumours does not appear to correlate with estrogen receptor (ER) status, it is differentially expressed in breast cancer cell lines where ER-negative cells have lower LKB1 expression than ER-positive cells. The present study aimed to examine the effects of estradiol on LKB1 expression and activity in the ER-positive breast cancer cell line MCF-7. Results demonstrate that estradiol causes a dose-dependent decrease in LKB1 transcript and protein expression and consistent with this, a significant decrease in the phosphorylation of the LKB1 target AMPK (P ≤ 0.05). In order to assess whether effects of estradiol were due to effects on ERα binding to the STK11 promoter, ChIP was performed. Results demonstrate that ERα binds to the STK11 promoter in a ligand-independent manner and that this interaction is decreased in the presence of estradiol. Moreover, STK11 promoter activity is significantly decreased in the presence of estradiol (P ≤ 0.05). LKB1 transcript and IHC score were assessed in primary tumours of 18 patients and demonstrated no significant correlation with ER status (n = 18). Our results thereby provide a mechanism whereby LKB1 is decreased in ER-positive breast tumours.
肝激酶 B1（LKB1）由 STK11 基因编码，作为一种肿瘤抑制因子和能量平衡的调节剂。与正常乳腺上皮相比，LKB1 在原发性乳腺癌肿瘤中的表达降低。尽管其在原发性肿瘤中的表达似乎与雌激素受体（ER）状态无关，但在乳腺癌细胞系中，ER 阴性细胞的 LKB1 表达低于 ER 阳性细胞，其表达存在差异。本研究旨在研究雌二醇对 ER 阳性乳腺癌细胞系 MCF-7 中 LKB1 表达和活性的影响。结果表明，雌二醇导致 LKB1 转录本和蛋白表达的剂量依赖性降低，与此一致，LKB1 靶标 AMPK 的磷酸化显著降低（P ≤ 0.05）。为了评估雌二醇的作用是否是由于其对 ERα 与 STK11 启动子结合的影响，进行了 ChIP 实验。结果表明，ERα 以配体非依赖性方式与 STK11 启动子结合，而在雌二醇存在下，这种相互作用减少。此外，在雌二醇存在下，STK11 启动子活性显著降低（P ≤ 0.05）。在 18 名患者的原发性肿瘤中评估了 LKB1 转录本和 IHC 评分，与 ER 状态（n = 18）无显著相关性。因此，我们的结果提供了一种机制，即 ER 阳性乳腺癌肿瘤中 LKB1 减少。
