Protein‑ and growth‑modulatory effects of carcinoma‑associated fibroblasts on breast cancer cells: Role of interleukin‑6.

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 ERα‑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.