title: Insulin-like growth factor-I inhibits progesterone receptor expression in breast cancer cells via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway: progesterone receptor as a potential indicator of growth factor activity in breast cancer.
abstract: Although interactions between estrogen and growth factor signaling pathways have been studied extensively, how growth factors and progesterone regulate each other is less clear. In this study, we found that IGF-I sharply lowers progesterone receptor (PR) mRNA and protein levels in breast cancer cells. Other growth factors, such as epidermal growth factor, also showed the same effect. The decrease of PR levels was associated with reduced PR activity. Unlike progestins, IGF-I does not utilize the proteasome for down-regulating PR. Instead, the IGF-I-mediated decrease in PR levels is via an inhibition of PR gene transcription. In addition, the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway was found to be specifically involved in this IGF-I effect. Our data also suggest that the IGF-I down-regulation of PR is not mediated via a reduction of estrogen receptor (ER) levels or activity. First, IGF-I induced ligand-independent ER activity while reducing ER-dependent PR levels. Second, whereas PR and cyclin D1 are both ER up-regulated, IGF-I increased cyclin D1 levels while decreasing PR levels. Third, constitutively active PI3K or Akt induced ER activity but reduced PR levels and activity. Taken together, our data indicate that IGF-I inhibits PR expression in breast cancer cells via the PI3K/Akt/mTOR pathway. Because low or absent PR in primary breast cancer is associated with poor prognosis and response to hormone therapy, our results suggest that low PR status may serve as an indicator of activated growth factor signaling in breast tumor cells, and therefore of an aggressive tumor phenotype and resistance against hormonal therapy.
authors.affiliation: Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Cui
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: Wanleng
authors.initials: W
authors.lastname: Deng
authors.forename: Steffi
authors.initials: S
authors.lastname: Oesterreich
authors.forename: Yiling
authors.initials: Y
authors.lastname: Lu
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Adrian V
authors.initials: AV
authors.lastname: Lee
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D019938:Cyclin D1 / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006133:Growth Substances / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011237:Predictive Value of Tests; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D011980:Receptors, Progesterone / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D019938:Cyclin D1; D004791:Enzyme Inhibitors; D006133:Growth Substances; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C494918:AKT1 protein, human