title: Physiologic levels of 2-methoxyestradiol interfere with nongenomic signaling of 17beta-estradiol in human breast cancer cells.
abstract: OBJECTIVE
  The purpose of this investigation is to determine the effects of physiologic levels (10-50 nmol/L) of 2-methoxyestradiol (2ME) on the growth of estrogen receptor (ER)-positive breast cancer cells and provide insights into its mechanism(s) of action.
  
  
  METHODS
  Using the ERalpha-positive breast cancer cells, we studied the effects of 2ME on cell proliferation and cell signaling. Our hypothesis is that 17beta-estradiol (E(2)) and 2ME can affect shared cell signaling pathways, leading to different outcomes in cell proliferation, depending on the absence/presence of E(2).
  
  
  RESULTS
  E(2) stimulated the growth of MCF-7 and T-47 D cells and induced Akt phosphorylation, a nongenomic signaling pathway. In the absence of E(2), 10 to 50 nmol/L of 2ME enhanced cell growth and Akt phosphorylation. However, in the presence of E(2), 2ME inhibited E(2)-induced cell growth and prevented E(2)-induced Akt phosphorylation. Confocal microscopic studies showed that 2ME inhibited subcellular distribution of ERalpha in response to E(2) in MCF-7 and T-47D cells. 2ME also down-regulated E(2)-induced increases in cyclic AMP and ornithine decarboxylase activity. In addition, treatment of MCF-7 cells with 2ME in the presence of E(2) resulted in a decrease in ERalpha level by 72 hours. Accelerated down-regulation of ERalpha may contribute to growth inhibition in the presence of E(2)/2ME combinations. In contrast, a concentration of up to 2.5 mumol/L 2ME had no effect on the growth of ER-negative SK-BR-3 cells, either in the presence or absence of E(2).
  
  
  CONCLUSIONS
  Our results provide evidence for the nongenomic action of 2ME in ER-positive cells. In the presence of E(2), 2ME suppressed E(2)-induced cell growth, Akt signaling, and generation of cyclic AMP, whereas it acted as an estrogen in the absence of E(2). The intriguing growth-stimulatory and growth-inhibitory effects of 2ME on breast cancer cells suggests the need for its selective use in patients.
authors.affiliation: Department of Medicine, Environmental and Occupational Health Sciences Institute and The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
authors.forename: Veena
authors.initials: V
authors.lastname: Vijayanathan
authors.forename: Sripriya
authors.initials: S
authors.lastname: Venkiteswaran
authors.forename: Sandhya K
authors.initials: SK
authors.lastname: Nair
authors.forename: Arti
authors.initials: A
authors.lastname: Verma
authors.forename: T J
authors.initials: TJ
authors.lastname: Thomas
authors.forename: Bao Ting
authors.initials: BT
authors.lastname: Zhu
authors.forename: Thresia
authors.initials: T
authors.lastname: Thomas
mesh_terms: D000077584:2-Methoxyestradiol; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000242:Cyclic AMP / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000187:drug effects; D005260:Female; D006801:Humans; D010766:Phosphorylation; D011073:Polyamines / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D047628:Estrogen Receptor alpha; D011073:Polyamines; D004958:Estradiol; D000077584:2-Methoxyestradiol; D000242:Cyclic AMP