Campbell and Moorehead BMC Cancer 2011, 11:480 http://www.biomedcentral.com/1471-2407/11/480 R E S E A R C H A R T I C L E Open Access Mammary tumors that become independent of the type I insulin-like growth factor receptor express elevated levels of platelet-derived growth factor receptors Craig I Campbell and Roger A Moorehead* Abstract Background: Targeted therapies are becoming an essential part of breast cancer treatment and agents targeting the type I insulin-like growth factor receptor (IGF-IR) are currently being investigated in clinical trials. One of the limitations of targeted therapies is the development of resistant variants and these variants typically present with unique gene expression patterns and characteristics compared to the original tumor. Results: MTB-IGFIR transgenic mice, with inducible overexpression of the IGF-IR were used to model mammary tumors that develop resistance to IGF-IR targeting agents. IGF-IR independent mammary tumors, previously shown to possess characteristics associated with EMT, were found to express elevated levels of PDGFRa and PDGFRb. Furthermore, these receptors were shown to be inversely expressed with the IGF-IR in this model. Using cell lines derived from IGF-IR-independent mammary tumors (from MTB-IGFIR mice), it was demonstrated that PDGFRa and to a lesser extent PDGFRb was important for cell migration and invasion as RNAi knockdown of PDGFRa alone or PDGFRa and PDGFRb in combination, significantly decreased tumor cell migration in Boyden chamber assays and suppressed cell migration in scratch wound assays. Somewhat surprisingly, concomitant knockdown of PDGFRa and PDGFRb resulted in a modest increase in cell proliferation and a decrease in apoptosis. Conclusion: During IGF-IR independence, PDGFRs are upregulated and function to enhance tumor cell motility. These results demonstrate a novel interaction between the IGF-IR and PDGFRs and highlight an important, therapeutically relevant pathway, for tumor cell migration and invasion. Keywords: IGF-IR, PDGFR, Breast cancer, Migration, Resistance Background Targeting receptor tyrosine kinases (RTKs) for the treat- ment of breast cancer has emerged as a promising direc- tion for the management of this disease. However, a major drawback of this line of treatment is the propen- sity of tumors to acquire resistance. For example, a number of mechanisms have been identified as media- tors of resistance to the commonly used Her2-directed therapeutic trastuzumab (reviewed in [1]). Therefore, a powerful tool for overcoming this shortcoming and * Correspondence: rmoorehe@uoguelph.ca Department of Biomedical Sciences, University of Guelph, 50 Stone Rd. E, N1G2W1 Guelph, ON, Canada optimizing the use of such compounds will be under- standing mechanisms of resistance. The insulin-like growth factor (IGF)-axis comprises one such RTK signalling pathway heavily implicated in the progression of breast cancer and as such holds pro- mise for therapeutic targeting. Upon activation by ligand (IGF-I or IGF-II), the IGF-IR undergoes tyrosine phos- phorylation, subsequently signaling through a number of downstream pathways including MAPK and PI-3K/Akt. The mitogenicity of this receptor is well established, and is well known to contribute to transformation of normal mammary epithelial cells [2]. Effective targeting of this pathway was established in a number of xenograft mod- els of breast cancer [3-7]. Activation of the IGF-IR is © 2011 Campbell and Moorehead; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.