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Suppression of heat shock protein 27 induces long-term dormancy in human breast cancer.

Abstract

The mechanisms underlying tumor dormancy have been elusive and not well characterized. We recently published an experimental model for the study of human tumor dormancy and the role of angiogenesis, and reported that the angiogenic switch was preceded by a local increase in VEGF-A and basic fibroblast growth factor. In this breast cancer xenograft model (MDA-MB-436 cells), analysis of differentially expressed genes revealed that heat shock protein 27 (HSP27) was significantly up-regulated in angiogenic cells compared with nonangiogenic cells. The effect of HSP27 down-regulation was further evaluated in cell lines, mouse models, and clinical datasets of human patients with breast cancer and melanoma. Stable down-regulation of HSP27 in angiogenic tumor cells was followed by long-term tumor dormancy in vivo. Strikingly, only 4 of 30 HSP27 knockdown xenograft tumors initiated rapid growth after day 70, in correlation with a regain of HSP27 protein expression. Significantly, no tumors escaped from dormancy without HSP27 expression. Down-regulation of HSP27 was associated with reduced endothelial cell proliferation and decreased secretion of VEGF-A, VEGF-C, and basic fibroblast growth factor. Conversely, overexpression of HSP27 in nonangiogenic cells resulted in expansive tumor growth in vivo. By clinical validation, strong HSP27 protein expression was associated with markers of aggressive tumors and decreased survival in patients with breast cancer and melanoma. An HSP27-associated gene expression signature was related to molecular subgroups and survival in breast cancer. Our findings suggest a role for HSP27 in the balance between tumor dormancy and tumor progression, mediated by tumor-vascular interactions. Targeting HSP27 might offer a useful strategy in cancer treatment.

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  • Authors

    Straume O, Shimamura T, Lampa MJ, Carretero J, Øyan AM, Jia D, Borgman CL, Soucheray M, Downing SR, Short SM, Kang SY, Wang S, Chen L, Collett K, Bachmann I, Wong KK, Shapiro GI, Kalland KH, Folkman J, Watnick RS, Akslen LA, Naumov GN

    Source

    Proceedings of the National Academy of Sciences of the United States of America 109:22 2012 May 29 pg 8699-704

    MeSH

    Animals
    Blotting, Western
    Breast Neoplasms
    Cell Line, Tumor
    Cell Proliferation
    Cells, Cultured
    Down-Regulation
    Female
    Fibroblast Growth Factor 2
    Gene Expression Profiling
    Gene Expression Regulation, Neoplastic
    HSP27 Heat-Shock Proteins
    Human Umbilical Vein Endothelial Cells
    Humans
    Male
    Mammary Neoplasms, Experimental
    Mice
    Mice, SCID
    Neovascularization, Pathologic
    Oligonucleotide Array Sequence Analysis
    Reverse Transcriptase Polymerase Chain Reaction
    Time Factors
    Transplantation, Heterologous
    Vascular Endothelial Growth Factor A
    Vascular Endothelial Growth Factor C

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't
    Research Support, U.S. Gov't, Non-P.H.S.

    Language

    eng

    PubMed ID

    22589302