Annexin-1 regulates growth arrest induced by high levels of estrogen in MCF-7 breast cancer cells.
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.
Ang
Emily Zhao-Feng
EZ
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Nguyen
Hung Thanh
HT
Sim
Hui-Ling
HL
Putti
Thomas C
TC
Lim
Lina H K
LH
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017305:Annexin A1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D002273:Carcinogens / Q000633:toxicity; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000378:metabolism / Q000473:pathology; D018276:Carcinoma, Medullary / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015854:Up-Regulation
D015127:9,10-Dimethyl-1,2-benzanthracene; D017305:Annexin A1; D002273:Carcinogens; D017362:Cyclic AMP Response Element-Binding Protein; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047628:Estrogen Receptor alpha; D004967:Estrogens; D008156:Luciferases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019869:Phosphatidylinositol 3-Kinases; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C506487:ESR1 protein, human