MilliporeSigma

Dickkopf-1 is regulated by the mevalonate pathway in breast cancer.

Breast cancer research : BCR (2014-02-18)
Tilman D Rachner, Andy Göbel, Stefanie Thiele, Martina Rauner, Peggy Benad-Mehner, Peyman Hadji, Thomas Bauer, Michael H Muders, Gustavo B Baretton, Franz Jakob, Regina Ebert, Martin Bornhäuser, Christian Schem, Lorenz C Hofbauer
ABSTRACT

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

MATERIALS
Product Number
Brand
Product Description

Supelco
Hydrogen peroxide solution, ≥30%, for trace analysis
Sigma-Aldrich
Hydrogen peroxide solution, 34.5-36.5%
Millipore
Hydrogen peroxide solution, 3%, suitable for microbiology
Sigma-Aldrich
Hydrogen peroxide solution, 30 % (w/w) in H2O, contains stabilizer
Sigma-Aldrich
MISSION® esiRNA, targeting human CDC42
Sigma-Aldrich
Hydrogen peroxide solution, contains potassium stannate as inhibitor, 30-32 wt. % in water, semiconductor grade, 99.999% trace metals basis
Sigma-Aldrich
MISSION® esiRNA, targeting mouse Cdc42
Sigma-Aldrich
Hydrogen peroxide solution, tested according to Ph. Eur.
Supelco
Hydrogen peroxide solution, 30 % (w/w), for ultratrace analysis
Sigma-Aldrich
Hydrogen peroxide solution, contains ~200 ppm acetanilide as stabilizer, 3 wt. % in H2O
Sigma-Aldrich
Hydrogen peroxide solution, 50 wt. % in H2O, stabilized
Sigma-Aldrich
Hydrogen peroxide solution, contains inhibitor, 35 wt. % in H2O
Sigma-Aldrich
Hydrogen Peroxide Solution, 30% (w/w), puriss. p.a., reag. ISO, reag. Ph. Eur.
Sigma-Aldrich
Hydrogen peroxide solution, purum p.a., ≥35% (RT)
Sigma-Aldrich
Hydrogen peroxide solution, contains inhibitor, 30 wt. % in H2O, ACS reagent
Sigma-Aldrich
Hydrogen peroxide solution, contains inhibitor, 30 wt. % in H2O, meets USP testing specifications
Sigma-Aldrich
β-D-Allose, rare aldohexose sugar
Sigma-Aldrich
Geranylgeranyl pyrophosphate ammonium salt, solution, ≥95% (TLC), ~1 mg/mL in methanol: NH4OH (7:3)
Sigma-Aldrich
DKK-1 human, recombinant, expressed in HEK 293 cells, ≥97% (SDS-PAGE), ≥97% (HPLC), suitable for cell culture