TNFα resistance in MCF-7 breast cancer cells is associated with altered subcellular localization of p21^CIP1 and p27^KIP1

Dear Editor,

Tumor necrosis factor alpha (TNFα) is a pleiotropic cytokine that plays an important role in immunity and inflammation as well as in the control of cell proliferation, differentiation, and apoptosis. TNFα is produced mainly by macrophages and enhances tumor regression mediated by cytotoxic T cells.^{1, 2} Although systemic toxicity dashed early hopes of clinical use of this cytokine as an antitumor agent, the development of new strategies such as site-directed delivery of TNFα in combination with chemotherapy drugs significantly reduced side effects and enhanced antitumor activity.^{3, 4} Unfortunately, a subset of tumor cells responds poorly or become resistant to TNFα, thus evading the host's immune defense. Breast cancer cells isolated from ∼70% of patients are sensitive to TNF-induced apoptosis. Resistance to TNF is observed in the remaining patient samples, which are also cross-resistant to the chemotherapeutic drug, doxorubicin.⁵ Although we and others have demonstrated that NF-κB plays a role in TNF-resistance of breast cancers,^{6, 7} an NF-κB-independent TNF resistance mechanism in breast cancer has not been described.

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