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Retinoic acid-induced growth arrest of MCF-7 cells involves the selective regulation of the IRS-1/PI 3-kinase/AKT pathway

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Abstract

In the MCF-7 breast cancer cell line, insulin-like growth factors (IGFs) are known to elicit antiproliferative actions via the insulin receptor substrate-1 (IRS-1)/PI 3-kinase/AKT pathway. All-trans retinoic acid (RA) is a potent inhibitor of MCF-7 cell proliferation, but the mechanism by which growth regulation is achieved remains unclear. We investigated the effects of RA on the regulation of the IGF-IR and its key signaling elements: IRS-1, IRS-2, and SHC. Treatment of MCF-7 cells with RA caused a significant reduction in IRS-1 protein and tyrosine phosphorylation levels at a concentration and time consistent with RA-mediated growth inhibition. IRS-1 regulation is selective, as RA did not influence IRS-2 or SHC levels. Downstream signaling events were also selectively reduced, as RA abrogated IGF-I-stimulated AKT activation but did not alter erk1/2 activation. To confirm the importance of IRS-1 regulation by RA, we examined the response to RA in MCF-7 cells overexpressing IGF-IR and IRS-1. RA resistance was observed in MCF-7 cells overexpressing IRS-1 but not IGF-IR. This suggests that RA-mediated growth inhibition requires the selective downregulation of IRS-1 and AKT. Therapeutic agents targeting the IRS-1/PI 3-kinase/AKT pathway may enhance the cytostatic effects of RA in breast cancer, since overexpression of IRS-1 and AKT have been reported in primary breast tumors.

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Acknowledgements

We thank Dr Ewa Surmacz for helpful discussion and for providing the MCF-7 cells stably transfected with various IGF signaling components. This work was supported by a predoctoral fellowship award from the US Army Medical Research and Material Command Breast Cancer Research Program (award number DAMD1701-1-0320 to SV del Rincón) and a grant from the Canadian Breast Cancer Research Initiative. Wilson H Miller Jr is an Investigator of the Canadian Institutes of Health Research.

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  1. Departments of Oncology and Medicine, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital and McGill University, Montreal, Quebec, Canada

    Sonia V del Rincón, Caroline Rousseau, Ratna Samanta & Wilson H Miller Jr

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  1. Sonia V del Rincón
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  4. Wilson H Miller Jr
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Correspondence to Wilson H Miller Jr.

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del Rincón, S., Rousseau, C., Samanta, R. et al. Retinoic acid-induced growth arrest of MCF-7 cells involves the selective regulation of the IRS-1/PI 3-kinase/AKT pathway. Oncogene 22, 3353–3360 (2003). https://doi.org/10.1038/sj.onc.1206485

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