Wild-Type N-Ras, Overexpressed in Basal-like Breast Cancer, Promotes Tumor Formation by Inducing IL-8 Secretion via JAK2 Activation
Journal
Cell Reports
Journal Volume
12
Journal Issue
3
Pages
511-524
Date Issued
2015
Author(s)
Zheng Z.-Y.
Tian L.
Bu W.
Fan C.
Gao X.
Wang H.
Li Y.
Lewis M.T.
Edwards D.
Zwaka T.P.
Hilsenbeck S.G.
Medina D.
Perou C.M.
Creighton C.J.
Zhang X.H.-F.
Chang E.C.
Abstract
Basal-like breast cancers (BLBCs) are aggressive, and their drivers are unclear. We have found that wild-type N-RAS is overexpressed in BLBCs but not in other breast cancer subtypes. Repressing N-RAS inhibits transformation and tumor growth, whereas overexpression enhances these processes even in preinvasive BLBC cells. We identified N-Ras-responsive genes, most of which encode chemokines; e.g., IL8. Expression levels of these chemokines and N-RAS in tumors correlate with outcome. N-Ras, but not K-Ras, induces IL-8 by binding and activating the cytoplasmic pool of JAK2; IL-8 then acts on both the cancer cells and stromal fibroblasts. Thus, BLBC progression is promoted by increasing activities of wild-type N-Ras, which mediates autocrine/paracrine signaling that can influence both cancer and stroma cells. ? 2015 The Authors.
SDGs
Other Subjects
interleukin 8; Janus kinase 2; guanosine triphosphatase; interleukin 8; Janus kinase 2; animal cell; animal experiment; animal model; Article; autocrine effect; basal like breast cancer; breast cancer cell line; cancer growth; controlled study; cytokine release; enzyme activation; female; fibroblast; gene control; gene overexpression; gene repression; genetic association; intracellular signaling; malignant transformation; mouse; nonhuman; oncogene K ras; oncogene N ras; paracrine signaling; priority journal; protein expression; protein function; protein protein interaction; animal; breast tumor; enzymology; genetics; human; metabolism; nude mouse; oncogene ras; signal transduction; transgenic mouse; tumor cell line; Animals; Breast Neoplasms; Cell Line, Tumor; Female; Genes, ras; GTP Phosphohydrolases; Humans; Interleukin-8; Janus Kinase 2; Mice; Mice, Nude; Mice, Transgenic; Signal Transduction
Publisher
Elsevier B.V.
Type
journal article