title: 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.
abstract: 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.
authors.affiliation: Ela Kodesz Institute for Research on Cancer Development and Prevention, Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978 Tel Aviv, Israel.
authors.forename: Polina
authors.initials: P
authors.lastname: Weitzenfeld
authors.affiliation: Ela Kodesz Institute for Research on Cancer Development and Prevention, Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978 Tel Aviv, Israel.
authors.forename: Nurit
authors.initials: N
authors.lastname: Meron
authors.affiliation: Ela Kodesz Institute for Research on Cancer Development and Prevention, Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978 Tel Aviv, Israel.
authors.forename: Tal
authors.initials: T
authors.lastname: Leibovich-Rivkin
authors.affiliation: Ela Kodesz Institute for Research on Cancer Development and Prevention, Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978 Tel Aviv, Israel.
authors.forename: Tsipi
authors.initials: T
authors.lastname: Meshel
authors.affiliation: Ela Kodesz Institute for Research on Cancer Development and Prevention, Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978 Tel Aviv, Israel.
authors.forename: Adit
authors.initials: A
authors.lastname: Ben-Baruch
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002470:Cell Survival; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D004815:Epidermal Growth Factor / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D018874:Spheroids, Cellular / Q000378:metabolism; D059016:Tumor Microenvironment; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004967:Estrogens; D019012:Integrin beta1; D014409:Tumor Necrosis Factor-alpha; D004815:Epidermal Growth Factor