Progression of luminal breast tumors is promoted by ménage à trois between the inflammatory cytokine TNFα and the hormonal and growth-supporting arms of the tumor microenvironment

Mediators Inflamm. 2013:2013:720536. doi: 10.1155/2013/720536. Epub 2013 Dec 4.


Breast cancer progression is strongly linked to inflammatory processes, aggravating disease course. The impacts of the inflammatory cytokine TNF α on breast malignancy are not fully substantiated, and they may be affected by cooperativity between TNF α and other protumoral mediators. Here, we show that together with representatives of other important arms of the tumor microenvironment, estrogen (hormonal) and EGF (growth-supporting), TNF α potently induced metastasis-related properties and functions in luminal breast tumor cells, representing the most common type of breast cancer. Jointly, TNFα + Estrogen + EGF had a stronger effect on breast cancer cells than each element alone, leading to the following: (1) extensive cell spreading and formation of FAK/paxillin-enriched cellular protrusions; (2) elevated proportion of tumor cells coexpressing high levels of CD44 and β 1 and VLA6; (3) EMT and cell migration; (4) resistance to chemotherapy; (5) release of protumoral factors (CXCL8, CCL2, MMPs). Importantly, the tumor cells used in this study are known to be nonmetastatic under all conditions; nevertheless, they have acquired high metastasizing abilities in vivo in mice, following a brief stimulation by TNFα + Estrogen + EGF. These dramatic findings indicate that TNF α can turn into a strong prometastatic factor, suggesting a paradigm shift in which clinically approved inhibitors of TNFα would be applied in breast cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Cell Survival
  • Disease Progression
  • Enzyme-Linked Immunosorbent Assay
  • Epidermal Growth Factor / metabolism
  • Estrogens / metabolism
  • Female
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Inflammation / metabolism
  • Integrin beta1 / metabolism
  • MCF-7 Cells
  • Mice
  • Mice, Nude
  • Microscopy, Confocal
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Spheroids, Cellular / metabolism
  • Tumor Microenvironment*
  • Tumor Necrosis Factor-alpha / metabolism*


  • Antineoplastic Agents
  • Estrogens
  • Integrin beta1
  • Tumor Necrosis Factor-alpha
  • Epidermal Growth Factor