Fetuin-A Modulates Tumor Growth and Invasion in a Basal-like Triple Negative Breast Cancer Cell line, MDA-MB-468

The current research was designed to explore the novel role of fetuin-A in promoting growth and invasion in the triple negative breast cancer (TNBC) cell line MDA-MB-468. This subtype of TNBC, classified as basal-like, is associated with a worse clinical outcome when tumor cells exhibit high levels of ectopic fetuin-A expression, compared to tumors with lower levels of the protein. To investigate this further, the MDA-MB-468 cells were genetically modified to overexpress fetuin-A. These modified cells were then compared to control cells transfected with an empty vector to evaluate differences in invasive behavior.

A series of experiments was conducted to examine the effects of fetuin-A on cell adhesion, proliferation, and invasion under various conditions. These included serum-free media supplemented solely with fetuin-A, as well as complete media containing the full complement of growth factors. The results demonstrated that cells overexpressing fetuin-A displayed a marked increase in their ability to invade surrounding tissues. In parallel, an upregulation of Toll-like receptor 4 (TLR4) expression was observed in the fetuin-A-overexpressing cells, indicating a potential mechanistic link.

Further investigation into this relationship revealed that the interaction between fetuin-A and TLR4 is critical for driving both the growth and invasive capacity of these cancer cells. This was confirmed through the use of CLI-095 (resatorvid), a selective inhibitor of TLR4. Treatment with CLI-095 effectively suppressed the growth and invasion typically mediated by fetuin-A, underscoring the importance of this signaling axis.

In summary, the findings from these studies strongly indicate that fetuin-A contributes to the aggressive phenotype of TNBC cells by engaging the TLR4 signaling pathway. This fetuin-A–TLR4 network appears to be a key driver of both proliferation and invasion in this cancer subtype, suggesting its potential as a therapeutic target in managing aggressive forms of triple negative breast cancer.