Abstract
Insulin and insulin-like growth factor-1 (IGF1) have important roles in breast cancer development. The recent identification of nuclear insulin (INSR) and IGF1 (IGF1R) receptors provides a novel paradigm in the area of signal transduction. The fact that INSR and IGF1R can function as transcription factors, capable of binding DNA and controlling transcription, adds a new layer of biological complexity by conferring upon cell-surface receptors the ability to regulate genomic events. The present study was designed to assess the hypothesis that insulin and IGF1 pathways elicit differential effects on subcellular distribution and activation of ERK1/2 and AKT. To this end, MCF7 breast cancer-derived cell lines with specific INSR or IGF1R disruption were employed. In addition, small interfering RNA technology was used to specifically down-regulate INSR or IGF1R expression in T47D breast cancer cells. DNA affinity chromatography assays were conducted to address the specific binding of ERK1/2 and AKT to the IGF1R promoter region. We demonstrate that both INSR and IGF1R exhibit a nuclear localization in breast cancer-derived cells. In addition, the insulin and IGF1 pathways have different effects on the subcellular distribution (and, particularly, the nuclear presence) of ERK1/2 and AKT molecules. Both cytoplasmic mediators are capable of binding and transactivating the IGF1R promoter. In conclusion, our data are consistent with the notion that, in addition to their classical roles as targets for insulin-like molecules, both ERK1/2 and AKT are involved in transcriptional control of the IGF1R gene. This previously unrecognized regulatory loop may provide mechanistic advantages to breast cancer cells. Given the potential role of INSR and IGF1R as therapeutic targets in oncology, it will be of clinical relevance to address the future use of nuclear receptors and their downstream cytoplasmic mediators as biomarkers for INSR/IGF1R targeted therapy.
Highlights
Insulin and insulin-like growth factor-1 (IGF1) are regarded as important players in cancer biology [1,2]
Our data are consistent with the notion that, in addition to their classical roles as targets for insulin-like molecules, both ERK1/2 and AKT are involved in transcriptional control of the IGF1R gene
In view of the important roles of the INSR and IGF1R signaling pathways in breast cancer, we investigated the subcellular distribution of both receptors, as well as that of members of the extracellular signal-regulated kinases (ERK) and protein kinase B/AKT (PKB/AKT) families, two prototypical networks of cytoplasmic molecules involved in insulin/IGF1 signaling
Summary
Insulin and insulin-like growth factor-1 (IGF1) are regarded as important players in cancer biology [1,2]. A large body of clinical, experimental and epidemiological data supports the concept that activation of the insulin and IGF1 signaling pathways is a critical requisite for breast cancer progression [3,4,5]. Whereas the classical dogma maintains that insulin is responsible for metabolic types of action while IGF1 elicits primarily growth activities, there is a certain overlap in the spectrum of bioactivities of both hormones [6,7,8]. The interplay between insulin-like hormones and their receptors is an area of major basic and clinical interest [9]. It is still unknown, why INSR and IGF1R, despite sharing most of their downstream signaling molecules, exhibit, for the most part, distinct, well-defined functions
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