title: Deregulation of IGF-binding proteins -2 and -5 contributes to the development of endocrine resistant breast cancer in vitro.
abstract: Tamoxifen (TAM) remains the adjuvant therapy of choice for pre-menopausal women with ERα-positive breast cancer. Resistance and recurrence remain, however, a major challenge with many women relapsing and subsequently dying. The insulin-like growth factor (IGF) axis is involved in breast cancer pathogenesis and progression to endocrine resistant disease, but there is very little data on the expression and potential role of IGF-binding proteins (IGFBP) during acquisition of the resistant phenotype. The aim of this study was to determine the expression and functional role of IGFBP-2 and -5 in the development of TAM resistance (TamR) in vitro and to test retrospectively whether they were predictive of resistance in a tissue microarray of 77 women with primary breast cancers who relapsed on/after endocrine therapy and 193 who did not with long term follow up. Reciprocal expression of IGFBP-2 and IGFBP-5 was observed at both mRNA and protein level in TamR cells. IGFBP-2 expression was increased by 10-fold while IGFBP-5 was decreased by 100-fold, compared to TAM-sensitive control cells. shRNA-mediated silencing of IGFBP-2 in TamR cells restored TAM sensitivity suggesting a causal role for this gene in TamR. While silencing of IGFBP-5 in control cells had no effect on TAM sensitivity, it significantly increased the migratory capacity of these cells. Quantitative image analysis of immunohistochemical data failed, however, to demonstrate an effect of IGFBP2 expression in endocrine-relapsed patients. Likewise, IGFBP-2 and IGFBP-5 expression failed to show any significant associations with survival either in patients relapsing or those not relapsing on/after endocrine therapy. By contrast, in silico mining of a separate published dataset showed that in patients who received endocrine treatment, loss of expression of IGBP-5 was significantly associated with worse survival. Overall these data suggest that co-ordinated and reciprocal alteration in IGFBP-2 and -5 expression may play a role in the acquisition of endocrine resistance.
authors.affiliation: Department of Oral Biology, St James's University Hospital, Leeds, UK.|Leeds Institute of Cancer and Pathology, University of Leeds, UK.|Current address: Department of Breast Medical Oncology, MD Anderson Cancer Centre, University of Texas, Houston, USA.
authors.forename: Yousef
authors.initials: Y
authors.lastname: Hawsawi
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, UK.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Humphries
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Wright
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, UK.
authors.forename: Angelene
authors.initials: A
authors.lastname: Berwick
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, UK.
authors.forename: Mike
authors.initials: M
authors.lastname: Shires
authors.affiliation: Department of Oral Biology, St James's University Hospital, Leeds, UK.
authors.forename: Hanaa
authors.initials: H
authors.lastname: Al-Kharobi
authors.affiliation: Department of Oral Biology, St James's University Hospital, Leeds, UK.
authors.forename: Reem
authors.initials: R
authors.lastname: El-Gendy
authors.affiliation: St James's Institute of Oncology, St James's University Hospital, Leeds, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Jove
authors.affiliation: St James's Institute of Oncology, St James's University Hospital, Leeds, UK.|Leeds Institute of Cancer and Pathology, University of Leeds, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Twelves
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, UK.
authors.forename: Valerie
authors.initials: V
authors.lastname: Speirs
authors.affiliation: Department of Oral Biology, St James's University Hospital, Leeds, UK.
authors.forename: James
authors.initials: J
authors.lastname: Beattie
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D034622:RNA Interference; D018570:Risk Assessment; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000627:therapeutic use*; D013997:Time Factors; D014162:Transfection; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; C577903:IGFBP2 protein, human; D018971:Insulin-Like Growth Factor Binding Protein 2; D018975:Insulin-Like Growth Factor Binding Protein 5; D013629:Tamoxifen
keywords: IGF; breast cancer; endocrine resistance