title: Modulation of the insulin-like growth factor-I system by N-(4-hydroxyphenyl)-retinamide in human breast cancer cell lines.
abstract: The potent mitogenic activity of insulin-like growth factor I (IGF-I) on breast epithelium is inhibited by retinoic acid in oestrogen receptor-positive (ER+) breast cancer cell lines. We studied and compared the effects of N-(4-hydroxyphenyl)-retinamide (4-HPR) in terms of growth inhibition and modulation of the IGF-I system in ER+ (MCF-7) and oestrogen receptor-negative (ER-) (MDA-MB231) breast cancer cell lines. Treatment with 1-10 microM 4-HPR for up to 96 h induced a dose- and time-dependent inhibition of proliferation in both breast cancer cell lines. Induction of apoptosis was much more evident in MCF-7 than in MDA-MB231 cells (30-40% compared with 0-5% respectively at 5 microM for 48 h). Exogenous human recombinant IGF-I (hr-IGF-I)-stimulated cell proliferation was abolished by 1 microM 4-HPR in MCF-7 cells. Immunoreactive IGF-I-like protein concentration in conditioned medium was reduced by 38% in MCF-7 and by 90% in MDA-MB231 cell lines following treatment for 48 h with 5 microM 4-HPR. Western ligand blot analysis showed a reduction of IGF-binding protein 4 (BP4) and BP5 by 67% and 87%, respectively, in MCF-7, whereas IGF-BP4 and -BP1 were reduced by approximately 20% in MDA-MB231 cells. Exposure to 5 microM 4-HPR for 48 h inhibited [125I]IGF-I binding and Scatchard analysis revealed a decrease of more than 50% in maximum binding capacity (Bmax) and a reduced receptor number/cell in both cancer cell lines. Steady-state type I IGF-receptor mRNA levels were reduced by approximately 30% in both tumour cell lines. We conclude that 4-HPR induces a significant down-regulation of the IGF-I system in both ER+ (MCF-7) and ER- (MDA-MB231) breast cancer cell lines. These findings suggest that, in our model, interference with the ER signalling pathway is not the only mechanism of breast cancer growth inhibition by 4-HPR.
authors.affiliation: Department of Preclinical Oncology, National Institute for Cancer Research and Advanced Biotechnology Center, Genoa, Italy.
authors.forename: R E
authors.initials: RE
authors.lastname: Favoni
authors.forename: A
authors.initials: A
authors.lastname: de Cupis
authors.forename: S
authors.initials: S
authors.lastname: Bruno
authors.forename: D
authors.initials: D
authors.lastname: Yee
authors.forename: A
authors.initials: A
authors.lastname: Ferrera
authors.forename: P
authors.initials: P
authors.lastname: Pirani
authors.forename: A
authors.initials: A
authors.lastname: Costa
authors.forename: A
authors.initials: A
authors.lastname: Decensi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D017313:Fenretinide / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D011960:Receptors, Estrogen / Q000502:physiology; D017451:Receptors, Somatomedin / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D011960:Receptors, Estrogen; D017451:Receptors, Somatomedin; D017313:Fenretinide; D007334:Insulin-Like Growth Factor I