Dickkopf-1 is regulated by the mevalonate pathway in breast cancerReport as inadecuate




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Breast Cancer Research

, 16:R20

First Online: 14 February 2014Received: 15 August 2013Accepted: 05 February 2014DOI: 10.1186-bcr3616

Cite this article as: Rachner, T.D., Göbel, A., Thiele, S. et al. Breast Cancer Res 2014 16: R20. doi:10.1186-bcr3616

Abstract

IntroductionAmino-bisphosphonates and statins inhibit the mevalonate pathway, and may exert anti-tumor effects. The Wnt inhibitor dickkopf-1 DKK-1 promotes osteolytic bone lesions by inhibiting osteoblast functions and has been implicated as an adverse marker in multiple cancers. We assessed the effects of mevalonate pathway inhibition on DKK-1 expression in osteotropic breast cancer.

MethodsRegulation of DKK-1 by bisphosphonates and statins was assessed in human breast cancer cell lines, and the role of the mevalonate pathway and downstream targets was analyzed. Moreover, the potential of breast cancer cells to modulate osteoblastogenesis via DKK-1 was studied in mC2C12 cells. Clinical relevance was validated by analyzing DKK-1 expression in the tissue and serum of women with breast cancer exposed to bisphosphonates.

ResultsDKK-1 was highly expressed in receptor-negative breast cancer cell lines. Patients with receptor-negative tumors displayed elevated levels of DKK-1 at the tissue and serum level compared to healthy controls. Zoledronic acid and atorvastatin potently suppressed DKK-1 in vitro by inhibiting geranylgeranylation of CDC42 and Rho. Regulation of DKK-1 was strongest in osteolytic breast cancer cell lines with abundant DKK-1 expression. Suppression of DKK-1 inhibited the ability of breast cancer cells to block WNT3A-induced production of alkaline phosphates and bone-protective osteoprotegerin in preosteoblastic C2C12 cells. In line with the in vitro data, treatment of breast cancer patients with zoledronic acid decreased DKK-1 levels by a mean of 60% after 12 months of treatment.

ConclusionDKK-1 is a novel target of the mevalonate pathway that is suppressed by zoledronic acid and atorvastatin in breast cancer.

AbbreviationsALPalkaline phosphatase

BPbisphosphonate

DKK-1Dickkopf-1

ERestrogen receptor

FPPfarnesyl pyrophosphate

GAPDHglyceraldehyde 3-phosphate dehydrogenase

GGPPgeranyl-geranyl-pyrophosphate

OPGosteoprotegerin

PCRpolymerase chain reaction

siRNAsmall interfering RNA.

Electronic supplementary materialThe online version of this article doi:10.1186-bcr3616 contains supplementary material, which is available to authorized users.

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Author: Tilman D Rachner - Andy Göbel - Stefanie Thiele - Martina Rauner - Peggy Benad-Mehner - Peyman Hadji - Thomas Bauer - Mic

Source: https://link.springer.com/







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