title: GP88 (PC-Cell Derived Growth Factor, progranulin) stimulates proliferation and confers letrozole resistance to aromatase overexpressing breast cancer cells.
abstract: BACKGROUND
  Aromatase inhibitors (AI) that inhibit breast cancer cell growth by blocking estrogen synthesis have become the treatment of choice for post-menopausal women with estrogen receptor positive (ER+) breast cancer. However, some patients display de novo or acquired resistance to AI. Interactions between estrogen and growth factor signaling pathways have been identified in estrogen-responsive cells as one possible reason for acquisition of resistance. Our laboratory has characterized an autocrine growth factor overexpressed in invasive ductal carcinoma named PC-Cell Derived Growth Factor (GP88), also known as progranulin. In the present study, we investigated the role GP88 on the acquisition of resistance to letrozole in ER+ breast cancer cells
  
  
  METHODS
  We used two aromatase overexpressing human breast cancer cell lines MCF-7-CA cells and AC1 cells and their letrozole resistant counterparts as study models. Effect of stimulating or inhibiting GP88 expression on proliferation, anchorage-independent growth, survival and letrozole responsiveness was examined.
  
  
  RESULTS
  GP88 induced cell proliferation and conferred letrozole resistance in a time- and dose-dependent fashion. Conversely, naturally letrozole resistant breast cancer cells displayed a 10-fold increase in GP88 expression when compared to letrozole sensitive cells. GP88 overexpression, or exogenous addition blocked the inhibitory effect of letrozole on proliferation, and stimulated survival and soft agar colony formation. In letrozole resistant cells, silencing GP88 by siRNA inhibited cell proliferation and restored their sensitivity to letrozole.
  
  
  CONCLUSIONS
  Our findings provide information on the role of an alternate growth and survival factor on the acquisition of aromatase inhibitor resistance in ER+ breast cancer.
authors.affiliation: A&G Pharmaceutical Inc, 9130 Red Branch Rd, Columbia, MD, USA.
authors.forename: Tesfom
authors.initials: T
authors.lastname: Abrhale
authors.forename: Angela
authors.initials: A
authors.lastname: Brodie
authors.forename: Gauri
authors.initials: G
authors.lastname: Sabnis
authors.forename: Luciana
authors.initials: L
authors.lastname: Macedo
authors.forename: Changsheng
authors.initials: C
authors.lastname: Tian
authors.forename: Binbin
authors.initials: B
authors.lastname: Yue
authors.forename: Ginette
authors.initials: G
authors.lastname: Serrero
mesh_terms: D001141:Aromatase / Q000235:genetics / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D020868:Gene Silencing; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000077289:Letrozole; D009570:Nitriles / Q000494:pharmacology*; D000077153:Progranulins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D034741:RNA, Small Interfering / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D047072:Aromatase Inhibitors; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D009570:Nitriles; D000077153:Progranulins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D014230:Triazoles; D000077289:Letrozole; D001141:Aromatase