The Dual Role of Tumor Necrosis Factor-alpha (TNF-α) in Breast Cancer: Molecular Insights and Therapeutic Approaches

Background: Breast cancer is the most prevalent cancer among women worldwide and the fifth cause of death among all cancer patients. Breast cancer development is driven by genetic and epigenetic alterations, with the tumor microenvironment (TME) playing an essential role in disease progression and evolution through mechanisms like inflammation promotion. TNF-α is one of the essential pro-inflammatory cytokines found in the TME of breast cancer patients, being secreted both by stromal cells, mainly by tumor-associated macrophages, and by the cancer cells themselves. In this review, we explore the biological and clinical impact of TNF-α in all stages of breast cancer development. First of all, we explore the correlation between TNF-α expression levels at the tumor site or in plasma/serum of breast cancer patients and their respective clinical status and outcome. Secondly, we emphasize the role of TNF-α signaling in both estrogen-positive and -negative breast cancer cells. Thirdly, we underline TNF-α involvement in epithelial-to-mesenchymal transition (EMT) and metastasis of breast cancer cells, and we point out the contribution of TNF-α to the development of acquired drug resistance.

Conclusions: Collectively, these data reveal a pro-tumorigenic role of TNF-α during breast cancer progression and metastasis. We systemize the knowledge regarding TNF-α-related therapies in breast cancer, and we explain how TNF-α may act as both a target and a drug in different breast cancer therapeutic approaches. By corroborating the known molecular effects of TNF-α signaling in breast cancer cells with the results from several preclinical and clinical trials, including TNF-α-related clinical observations, we conclude that the potential of TNF-α in breast cancer therapy promises to be of great interest.