title: Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling.
abstract: Inflammatory mechanisms influence tumorigenesis and metastatic progression even in cancers whose aetiology does not involve pre-existing inflammation or infection, such as breast and prostate cancers. For instance, prostate cancer metastasis is associated with the infiltration of lymphocytes into advanced tumours and the upregulation of two tumour-necrosis-factor family members: receptor activator of nuclear factor-κB (RANK) ligand (RANKL) and lymphotoxin. But the source of RANKL and its role in metastasis have not been established. RANKL and its receptor RANK control the proliferation of mammary lobuloalveolar cells during pregnancy through inhibitor of nuclear factor-κB (IκB) kinase-α (IKK-α), a protein kinase that is needed for the self-renewal of mammary cancer progenitors and for prostate cancer metastasis. We therefore examined whether RANKL, RANK and IKK-α are also involved in mammary/breast cancer metastasis. Indeed, RANK signalling in mammary carcinoma cells that overexpress the proto-oncogene Erbb2 (also known as Neu), which is frequently amplified in metastatic human breast cancers, was important for pulmonary metastasis. Metastatic spread of Erbb2-transformed carcinoma cells also required CD4(+)CD25(+) T cells, whose major pro-metastatic function was RANKL production. Most RANKL-producing T cells expressed forkhead box P3 (FOXP3), a transcription factor produced by regulatory T cells, and were located next to smooth muscle actin (SMA)(+) stromal cells in mouse and human breast cancers. The dependence of pulmonary metastasis on T cells was replaceable by exogenous RANKL, which also stimulated pulmonary metastasis of RANK(+) human breast cancer cells. These results are consistent with the adverse impact of tumour-infiltrating CD4(+) or FOXP3(+) T cells on human breast cancer prognosis and suggest that the targeting of RANKL-RANK can be used in conjunction with the therapeutic elimination of primary breast tumours to prevent recurrent metastatic disease.
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, California 92093, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Tan
authors.forename: Weizhou
authors.initials: W
authors.lastname: Zhang
authors.forename: Amy
authors.initials: A
authors.lastname: Strasner
authors.forename: Sergei
authors.initials: S
authors.lastname: Grivennikov
authors.forename: Jin Q
authors.initials: JQ
authors.lastname: Cheng
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hoffman
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D016827:CD8 Antigens / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D016654:Genes, RAG-1 / Q000235:genetics; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000473:pathology; D000090063:Proto-Oncogene Mas; D053245:RANK Ligand / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D051858:Forkhead Transcription Factors; D051550:I-kappa B Kinase; D000090063:Proto-Oncogene Mas; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018719:Erb-b2 Receptor Tyrosine Kinases; C418974:FOXP3 protein, human; C000715470:MAS1 protein, human; C524056:Erbb2 protein, mouse