Inhibition of Interleukin-4, a Survival Factor for Breast Cancer Cells, as an Antimetastatic Approach
Final rept. 1 Sep 2009-31 Aug 2011
VANDERBILT UNIV MEDICAL CENTER NASHVILLE TN
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Our goal was to determine the effects on metastasis of deleting or inhibiting the receptor for interleukin-4 from breast tumor cells. We proposed three aims 1 Establish and characterize mammary tumor lines with the receptor for IL4 knocked down. 2 Determine the in vivo growth characteristics of IL4R-knockdown cells using spontaneous and experimental metastasis models 3 Determine the therapeutic efficacy of IL4 neutralizing antibody in combination with chemotherapy in a spontaneously-metastasizing model. We have completed all aims with the mammary tumor cell line 4T1, and obtained confirmatory data for aims 1 and 2 in a second cell line, PyVT-R221a. In vitro assays have indicated that IL4 receptor can promote proliferation and survival. When injected orthotopically in vivo, 4T1 mammary tumors showed no difference, whereas with PYVT-R221A cells, knockdown of IL4R completely abrogated tumor take. For both cell lines, metastatic tumor volume was significantly attenuated when tumor cell IL4R was knocked down The difference in behavior of primary mammary tumors may reflect the more aggressive properties of the 4T1 line. Disappointingly, combination therapy using paclitaxel with an IL4 neutralizing antibody showed no benefit in the 4T1 metastasis model. This was most likely due to ineffective dosing of agents, especially paclitaxel.
- Anatomy and Physiology
- Medicine and Medical Research