title: Effect of endocrine therapy on growth of T61 human breast cancer xenografts is directly correlated to a specific down-regulation of insulin-like growth factor II (IGF-II).
abstract: Insulin-like growth factors I and II (IGF-I and IGF-II) are potent mitogens for some human breast cancer cell lines, and expression of IGF-II mRNA in the oestrogen receptor-positive (ER+) and oestradiol (E2) stimulated human breast cancer cell line T47D is increased by E2, suggesting a role for IGF-II in the mitogenic response to E2. Very little information is available from the literature on the relation between growth inhibition by endocrine therapy and cellular production of IGF-II. Here we report on the effect of E2 and tamoxifen (TAM) on IGF-II mRNA and protein expression in the ER+T61 human breast cancer xenograft. Growth of the T61 tumour is inhibited by treatment with E2 and TAM. Ribonuclease (RNAse) protection assays with human- and mouse-specific IGF-II antisense probes were used to study the regulation of IGF-II mRNA by E2 and TAM in the tumour. IGF-II protein expression was studied by radioimmunoassay. Untreated T61 tumours have a high baseline expression of IGF-II mRNA. TAM treatment of T61 tumours, which results in inhibition of tumour growth without tumour regression, reduced IGF-II mRNA expression approximately 10-fold after 48 h of treatment. E2 treatment of T61 tumours, which results in tumour regression, was accompanied by a more pronounced decrease in IGF-II mRNA expression in the tumour cells; 96 h after initiation of E2 treatment, there was almost no detectable IGF-II mRNA. Analyses of IGF-II protein showed that both treatments significantly reduced the concentration of IGF-II protein in the tumours. This down-regulation was found to be specific for IGF-II, since analyses of the effect of E2 on the expression of IGF-I mRNA, 36B4 mRNA, transforming growth factor alpha(TGF-alpha) mRNA, and epidermal growth factor (EGF) receptor mRNA in T61 tumours did not reveal any down-regulation. To further study the relation between inhibition of tumour growth and down-regulation of IGF-II, we exposed T61 tumours to a monoclonal antibody, alpha-IR3, which abolishes the physiological effect of IGF-I and IGF-II by blocking the binding of both growth factors to the type I IGF receptor. Treatment with alpha-IR3 resulted in inhibition of tumour growth during treatment.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Finsen Laboratory, Copenhagen, Denmark.
authors.forename: N
authors.initials: N
authors.lastname: Brünner
authors.forename: D
authors.initials: D
authors.lastname: Yee
authors.forename: F G
authors.initials: FG
authors.lastname: Kern
authors.forename: M
authors.initials: M
authors.lastname: Spang-Thomsen
authors.forename: M E
authors.initials: ME
authors.lastname: Lippman
authors.forename: K J
authors.initials: KJ
authors.lastname: Cullen
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015536:Down-Regulation; D004958:Estradiol / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000187:drug effects; D013629:Tamoxifen / Q000627:therapeutic use; D014407:Tumor Cells, Cultured / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D012334:RNA, Neoplasm; D017527:Receptor, IGF Type 2; D013629:Tamoxifen; D004958:Estradiol; D007335:Insulin-Like Growth Factor II