No abstract

Previously we reported that lipopolysaccharide (LPS) treatment of murine mammary carcinomas resulted in decreased growth of the tumors. Here we show the decreased growth following LPS treatment was mediated through effects downstream of TLR4 and Myd88. Perhaps more notably, simply reducing TLR4 or Myd88 levels was sufficient to slow tumor growth rates. Moreover, reduced levels of Myd88 correlated with a significant reduction in lung metastasis as well as decreased CCL2 and CCL5 expression. To determine whether inhibiting Myd88 function could also alter tumor growth and chemokine expression we used a Myd88 homodimerization inhibitory peptide. Indeed, inhibiting Myd88 function in four different murine mammary carcinomas as well as the human breast cancer cell line MDA-MB-231 led to decreased growth as well as CCL2 and CCL5 expression. These data imply that Myd88 is important for growth and metastasis of breast cancer, and expression of at least two proinflammatory chemokines.

Previously we reported that lipopolysaccharide (LPS) treatment of murine mammary carcinomas resulted in decreased growth of the tumors in vivo, but not in vitro. Here we explored whether the effects of LPS were dependent upon TLR4 and Myd88 using RNA interference. Two clones with reduced TLR4 mRNA and protein expression and two clones with reduced Myd88 mRNA and protein expression were generated, as well as a clone expressing shRNA specific for lacZ as a control. Significantly, tumors with reduced TLR4 or Myd88 expression no longer exhibited decreased growth rates in vivo following LPS treatment indicating that the decreased growth rate of the 4T1 tumor following LPS treatment was mediated through effects downstream of TLR4 and Myd88. Perhaps more significantly, tumor cells with reduced levels of TLR4 or Myd88 exhibited slower growth rates in vitro and in vivo relative to the parental 4T1 and lacZ controls, and reducing Myd88 expression was sufficient to decrease CCL2 and CCL5 expression. To determine whether inhibiting Myd88 function was enough to alter tumor growth and CCL2 and CCL5 expression we used a Myd88 homodimerization inhibitory peptide. The data revealed that inhibiting Myd88 function was sufficient enough to impair growth of the tumor cells, and decrease constitutive expression of CCL2 and CCL5. These data imply that Myd88 is necessary for growth of murine mammary carcinomas, and expression of at least two proinflammatory chemokines.