Protein- And growth-modulatory effects of carcinoma-associated fibroblasts on breast cancer cells: Role of interleukin-6

Abstract

Carcinoma-associated fibroblasts (CAFs) secrete factors that increase the expression and/or activities of proteins in breast cancer cells and induce resistance to anti-estrogens, such as fulvestrant. A major factor is interleukin-6 (IL-6). This study demonstrated that, across estrogen receptor (ER) α-positive and -negative cell lines, recombinant human IL-6 (rhIL-6) mimicked most of the CAF-conditioned medium (CM)-induced changes in protein expression patterns; however, in most cases, it failed to recapitulate CAF-CM-triggered alterations in ERK1/2 and AKT activities. The ability of rhIL-6 to induce fulvestrant resistance was dependent upon the culture conditions. In 3D, but not in 2D cultures, rhIL-6 increased the survival of fulvestrant-treated cells, although not to the same extent as observed with CAF-CM. In 2D cultures, rhIL-6 acted in a pro-apoptotic manner and decreased the expression of ATP-binding cassette transporter G2 (ABCG2). The inhibition of the PI3K/AKT pathway had similar effects on apoptosis and ABCG2 expression, linking the failure of rhIL-6 to induce fulvestrant resistance to its inability to activate the PI3K/AKT pathway. In 3D cultures, both CAF-CM and rhIL-6 acted in an anti-apoptotic manner. These activities are likely independent on the PI3K/AKT pathway and ABCG2. Experiments on ERa-negative breast cancer cells revealed a growth-inhibitory effects of both CAF-CM and rhIL-6, which coincided with a reduction in the c-Myc level. These data suggest that IL-6 plays a role in several effects of CAF-CM, including alterations in protein expression patterns, fulvestrant resistance in 3D cultures and growth inhibition. By contrast, IL-6 is unlikely to be responsible for the CAF-CM-induced activation of the PI3K/AKT pathway and fulvestrant resistance in 2D cultures.