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Introduction The insulin-like growth factor (IGF) system comprises two ligands (IGF-1 and IGF-2) as well as the closely related hormone insulin, six binding proteins (IGFBP1-6), three receptors (type I and type II IGF and the insulin receptors) and
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action (see below). Binding of insulin analogues to the IR and the IGF1 receptor Structural modification of the insulin molecule may result in altered binding affinities and activities to the IR and/or the insulin-like growth factor 1 receptor (IGF1R). As
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1991 ). However, one growth factor receptor, insulin-like growth factor-1 receptor (IGF1R), has a convoluted history as a target for cancer therapy. Previously, IGF1R was considered a promising candidate for drug targeting due to its frequent
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levels of IGF-I were recently found to be associated with increased occurrence of adenomatous polyps and even advanced adenomas. In addition, colon cancer cells express high levels of IGF-I receptor (IGF-IR), a tyrosine kinase-containing transmembrane
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or transforming growth factor-α (TGF- α ) expression ( McClelland et al . 1996 ). Other important anti-proliferative effects of ICI include suppression of IGF receptor (IGF-IR) signalling, and previous reports have suggested that ICI, either
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Development of antiestrogen resistance is a major clinical problem, and therefore it is crucial to elucidate the mechanisms involved. To investigate whether gain-of-function or loss-of-function mechanisms was most likely to be involved, cell fusion between the antiestrogen-sensitive MCF-7 and the ICI 164384- and ICI 182780-resistant MCF-7/164(R)-5 cell lines was performed. Furthermore, a fusion cell line between the tamoxifen-resistant MCF-7/TAM(R)-1 and the MCF-7/164(R)-5 cell line was established. A thorough investigation of growth parameters and expression of selected proteins (estrogen receptor-alpha (ERalpha), progesterone receptor (PR), Bcl-2, IGF-binding protein-2 (IGFBP2) and IGF receptor Ialpha (IGF-IRalpha)) in the fusion partners and fusion cells revealed that both gain- and loss-of-function changes occurred, and that the mechanisms resulting in resistance to the two antiestrogens were different. This multi-factoriality of antiestrogen resistance is promising in relation to sequential treatment of breast cancer patients with different types of endocrine therapy. Furthermore, we found an association between antiestrogen resistance and reduced IGF-IRalpha expression. Overall, the data presented in this report support the usefulness of cell fusion to clarify the mechanisms involved in development of resistance to the pure antiestrogens ICI 182780 and ICI 164384 and the selective ER modulator tamoxifen and suggest IGF-IRalpha as a new sensitive marker for response to antiestrogen treatment.
Institute of Health and Biomedical Innovation, Vancouver Prostate Centre, Departments of Medicine and Oncology, Australian Prostate Cancer Research Centre – Queensland, Princess Alexandra Hospital, Queensland University of Technology, Level 1, Building 1, 199 Ipswich Road, Brisbane, Queensland 4102, Australia
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Institute of Health and Biomedical Innovation, Vancouver Prostate Centre, Departments of Medicine and Oncology, Australian Prostate Cancer Research Centre – Queensland, Princess Alexandra Hospital, Queensland University of Technology, Level 1, Building 1, 199 Ipswich Road, Brisbane, Queensland 4102, Australia
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( Paradowska et al . 2009 ); however, tumour IGF2 expression levels are not reflected in serum ( Rowlands et al . 2009 , 2012 ). IGF2 can signal through the IGF1 receptor (IGF1R) or via the insulin receptor (INSR) to elicit insulin-like signalling
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proteins (IGFBPs), receptors, and downstream signaling molecules, circulating growth factors constitute an endocrine system (usually referred to as the ‘IGF axis’) regulating metabolism and growth ( Stewart & Rotwein 1996 ). In addition, paracrine and
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Introduction The insulin-like growth factor (IGF) signalling axis involves the coordinated function of two ligands, IGF-I and IGF-II, three cell surface receptors, at least six high affinity binding proteins and binding protein
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, in the inhibition of the human epidermal growth factor (EGF) receptor-2 (HER2) in women with HER2-positive breast cancer and the blockade of EGF receptor kinase activity in non-small-cell lung cancer. In contrast, the insulin-like growth factor (IGF
