Autocrine role for HMGB1 and HSP60 in the growth of murine mammary carcinoma (127.13)

Abstract

Abstract Previously we reported that Myd88 contributed to growth, metastasis, and expression of CCL2 and CCL5 by mammary carcinoma implying that constitutive signaling through Myd88 contributes to tumor progression. To begin to decipher what may be inducing this signaling we focused on proteins that could function as damage associated molecular patterns (DAMPs) since DAMP expression has been reported in tumors, and certain DAMPs mediate effects through toll-like receptors. A screen of mammary carcinoma for DAMP expression showed HMGB1 and HSP60 were significantly elevated relative to normal mammary epithelium. Although suppression of either HMGB1 or HSP60 using RNAi reduced growth of the tumor cells, a significant reduction in growth as well as CCL2 expression was only found when both DAMPs were targeted. Since, besides their ability to function as DAMPs, HMGB1 and HSP60 have important roles in normal cellular functions we used blocking antibodies to determine whether these DAMPs were mediating effects in an autocrine manner. Indeed, antibodies to these DAMPs inhibited growth of the tumor cells, and analysis using a Myd88 inhibitory peptide suggested that HMGB1 mediated effects in a Myd88 dependent manner, while HSP60 mediated effects in a Myd88 independent manner. Collectively, these data show that mammary carcinoma overexpress HMGB1 and HSP60 relative to normal mammary epithelium, their expression influences tumor growth, and the effects of HMGB1 are dependent upon Myd88.