Abstract
BackgroundTargeted 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.ResultsMTB-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 PDGFRα and PDGFRβ. 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 PDGFRα and to a lesser extent PDGFRβ was important for cell migration and invasion as RNAi knockdown of PDGFRα alone or PDGFRα and PDGFRβ in combination, significantly decreased tumor cell migration in Boyden chamber assays and suppressed cell migration in scratch wound assays. Somewhat surprisingly, concomitant knockdown of PDGFRα and PDGFRβ resulted in a modest increase in cell proliferation and a decrease in apoptosis.ConclusionDuring 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.
Highlights
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
A DNA microarray was performed on wild type mammary tissue, mammary tumors induced by high levels of the IGF-IR transgene and mammary tumors that resumed growth following IGF-IR transgene downregulation that only expressed low levels of IGF-IR
The microarray data indicated that both PDGFRa and PDGFRb were upregulated in the IGF-IR-independent, recurrent tumors compared to the IGF-IR-dependent, primary tumors [14]
Summary
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. 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 promise for therapeutic targeting. Activation of the IGF-IR is not correlated with any particular subtype of breast cancer [8] and offers the opportunity for widespread use of targeted therapies Based on these observations, a number of drugs targeting this pathway are currently in clinical trials [9,10], including small molecule kinase inhibitors that block downstream signalling and monoclonal antibodies that block ligand receptor interactions [11]. While it is too early to determine the efficacy of such agents [9], it is of extreme importance to understand potential resistance mechanisms
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