Ang Emily Zhao-Feng, Nguyen Hung Thanh, Sim Hui-Ling, Putti Thomas C, Lim Lina H K
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Mol Cancer Res. 2009 Feb;7(2):266-74. doi: 10.1158/1541-7786.MCR-08-0147. Epub 2009 Feb 10.
Estrogen, a naturally occurring female steroid growth hormone, has been implicated as a major risk factor for the development of breast cancer. Recent research into this disease has also correlated Annexin-1 (ANXA1), a glucocorticoid-inducible protein, with the development of breast tumorigenesis. ANXA1 is lost in many cancers, including breast cancer, and this may result in a functional promotion of tumor growth. In this study, we investigated the expression of ANXA1 in MCF-7 cells treated with estrogen and the regulation of estrogen functions by ANXA1. Exposure of MCF-7 breast cancer cells to high physiologic levels (up to 100 nmol/L) of estrogen leads to an up-regulation of ANXA1 expression partially through the activation of cyclic AMP-responsive element binding protein and dependency on activation of the estrogen receptor. In addition, treatment of MCF-7 cells with physiologic levels of estrogen (1 nmol/L) induced proliferation, whereas high pregnancy levels of estrogen (100 nmol/L) induced a growth arrest of MCF-7 cells, associated with constitutive activation of extracellular signal-regulated kinase 1/2 and up-regulation of cell cycle arrest proteins such as p21(waf/cip). Silencing of ANXA1 with specific small interfering RNA reverses the estrogen-dependent proliferation as well as growth arrest and concomitantly modulates extracellular signal-regulated kinase 1/2 phosphorylation. We confirm that ANXA1 is lost in clinical breast cancer, indicating that the antiproliferative protective function of ANXA1 against high levels of estrogen may be lost. Finally, we show that ANXA1-deficient mice exhibit faster carcinogen-induced tumor growth. Our data suggest that ANXA1 may act as a tumor suppressor gene and modulate the proliferative functions of estrogens.
雌激素是一种天然存在的女性甾体生长激素，被认为是乳腺癌发生的主要危险因素。近期对该疾病的研究还发现，一种糖皮质激素诱导蛋白膜联蛋白-1（ANXA1）与乳腺肿瘤发生有关。ANXA1在包括乳腺癌在内的许多癌症中缺失，这可能导致肿瘤生长的功能性促进。在本研究中，我们研究了雌激素处理的MCF-7细胞中ANXA1的表达以及ANXA1对雌激素功能的调节。将MCF-7乳腺癌细胞暴露于高生理水平（高达100 nmol/L）的雌激素会导致ANXA1表达上调，部分是通过激活环磷酸腺苷反应元件结合蛋白以及依赖雌激素受体的激活。此外，用生理水平的雌激素（1 nmol/L）处理MCF-7细胞会诱导增殖，而高妊娠水平的雌激素（100 nmol/L）会诱导MCF-7细胞生长停滞，这与细胞外信号调节激酶1/2的组成性激活以及细胞周期停滞蛋白如p21（waf/cip）的上调有关。用特异性小干扰RNA沉默ANXA1可逆转雌激素依赖性增殖以及生长停滞，并同时调节细胞外信号调节激酶1/2的磷酸化。我们证实ANXA1在临床乳腺癌中缺失，这表明ANXA1对高水平雌激素的抗增殖保护功能可能丧失。最后，我们表明ANXA1缺陷小鼠表现出致癌物诱导的肿瘤生长更快。我们的数据表明，ANXA1可能作为一种肿瘤抑制基因，并调节雌激素的增殖功能。
