title: 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.
authors.affiliation: Vascular Biology Program, Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Oddbjørn
authors.initials: O
authors.lastname: Straume
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimamura
authors.forename: Michael J G
authors.initials: MJ
authors.lastname: Lampa
authors.forename: Julian
authors.initials: J
authors.lastname: Carretero
authors.forename: Anne M
authors.initials: AM
authors.lastname: Øyan
authors.forename: Di
authors.initials: D
authors.lastname: Jia
authors.forename: Christa L
authors.initials: CL
authors.lastname: Borgman
authors.forename: Margaret
authors.initials: M
authors.lastname: Soucheray
authors.forename: Sean R
authors.initials: SR
authors.lastname: Downing
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Short
authors.forename: Soo-Young
authors.initials: SY
authors.lastname: Kang
authors.forename: Souming
authors.initials: S
authors.lastname: Wang
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.forename: Karin
authors.initials: K
authors.lastname: Collett
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Bachmann
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: Karl Henning
authors.initials: KH
authors.lastname: Kalland
authors.forename: Judah
authors.initials: J
authors.lastname: Folkman
authors.forename: Randolph S
authors.initials: RS
authors.lastname: Watnick
authors.forename: Lars A
authors.initials: LA
authors.lastname: Akslen
authors.forename: George N
authors.initials: GN
authors.lastname: Naumov
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism
chemical_list: D055551:HSP27 Heat-Shock Proteins; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D016222:Fibroblast Growth Factor 2