title: Medroxyprogesterone acetate-driven increase in breast cancer risk might be mediated via cross-talk with growth factors in the presence of progesterone receptor membrane component-1.
abstract: BACKGROUND
  The WHI trial suggests an increase of breast cancer in postmenopausal women probably according to the progestogenic compound, i.e. medroxyprogesterone acetate (MPA). However, the mechanism for a possible carcinogenic effect of MPA remains unclear so far. Progesterone receptor membrane component-1 (PGRMC1) may be important in tumorigenesis and thus may increase breast cancer risk. We investigated the influence of MPA alone and in combination with growth factors on breast cancer cells overexpressing PGRMC1.
  
  
  METHODS
  MCF-7 cells were stably transfected with PGRMC1 expression plasmid (WT-12 cells). Cells transfected only with the vector were used as control cells (EVC-cells). Medroxyprogesterone acetate (MPA), norethisterone (NET) and progesterone (P) were tested alone and in combination with a mixture of growth factors. Cell proliferation was measured by MTT assay.
  
  
  RESULTS
  The growth factor mixture (GF) was able to induce cell proliferation in both cell types, however, the effect was much higher in the WT-12 cells. In WT-12 cells both MPA and NET alone significantly increased cell proliferation with values of 40% and 97%, respectively. Progesterone, however, had no effect. In combination with GF MPA significantly further enhanced cell proliferation as compared to the effect of MPA alone and GF alone in both cell lines. NET showed no further increase as compared to NET alone and P had no effect.
  
  
  CONCLUSIONS
  We could demonstrate a significant proliferative effect of MPA when combined with high concentrations of growth factors. This effect was more pronounced in breast cancer cells overexpressing PGRMC1. These results may be of clinical relevance since in the combined WHI trial an increased breast cancer risk was found during treatment with conjugated equine estrogens plus MPA.
authors.affiliation: Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China. jzhlzhj@hotmail.com
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: Qi
authors.initials: Q
authors.lastname: Yu
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.forename: Harald
authors.initials: H
authors.lastname: Seeger
authors.forename: Tanja
authors.initials: T
authors.lastname: Fehm
authors.forename: Michael A
authors.initials: MA
authors.lastname: Cahill
authors.forename: Alfred O
authors.initials: AO
authors.lastname: Mueck
authors.forename: Hans
authors.initials: H
authors.lastname: Neubauer
mesh_terms: D001943:Breast Neoplasms / Q000139:chemically induced* / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005562:Formazans / Q000032:analysis; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D061986:MCF-7 Cells; D017258:Medroxyprogesterone Acetate / Q000506:poisoning*; D008565:Membrane Proteins / Q000378:metabolism*; D009640:Norethindrone / Q000506:poisoning; D011374:Progesterone / Q000506:poisoning; D020239:Receptor Cross-Talk; D011980:Receptors, Progesterone / Q000378:metabolism*; D013778:Tetrazolium Salts / Q000032:analysis
chemical_list: D005562:Formazans; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C115296:PGRMC1 protein, human; D011980:Receptors, Progesterone; D013778:Tetrazolium Salts; C079782:MTT formazan; D011374:Progesterone; D017258:Medroxyprogesterone Acetate; D009640:Norethindrone
keywords: Breast cancer cells; Growth factors; Medroxyprogesterone acetate; Progesterone receptor membrane component-1; Proliferation