Rachner Tilman D, Göbel Andy, Thiele Stefanie, Rauner Martina, Benad-Mehner Peggy, Hadji Peyman, Bauer Thomas, Muders Michael H, Baretton Gustavo B, Jakob Franz, Ebert Regina, Bornhäuser Martin, Schem Christian, Hofbauer Lorenz C
Breast Cancer Res. 2014 Feb 14;16(1):R20. doi: 10.1186/bcr3616.
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.
氨基双膦酸盐和他汀类药物可抑制甲羟戊酸途径，并可能发挥抗肿瘤作用。Wnt抑制剂Dickkopf-1（DKK-1）通过抑制成骨细胞功能促进溶骨性骨病变，并且在多种癌症中被认为是一种不良标志物。我们评估了甲羟戊酸途径抑制对亲骨性乳腺癌中DKK-1表达的影响。
在人乳腺癌细胞系中评估双膦酸盐和他汀类药物对DKK-1的调节作用，并分析甲羟戊酸途径及其下游靶点的作用。此外，在mC2C12细胞中研究了乳腺癌细胞通过DKK-1调节成骨细胞生成的潜力。通过分析接受双膦酸盐治疗的乳腺癌女性组织和血清中的DKK-1表达来验证临床相关性。
DKK-1在受体阴性乳腺癌细胞系中高表达。与健康对照相比，受体阴性肿瘤患者在组织和血清水平上的DKK-1水平升高。唑来膦酸和阿托伐他汀在体外通过抑制CDC42和Rho的香叶基香叶基化有效地抑制了DKK-1。在具有丰富DKK-1表达的溶骨性乳腺癌细胞系中，DKK-1的调节作用最强。DKK-1的抑制抑制了乳腺癌细胞阻断WNT3A诱导的前成骨细胞C2C12细胞中碱性磷酸酶和骨保护素生成的能力。与体外数据一致，唑来膦酸治疗乳腺癌患者12个月后，DKK-1水平平均降低60%。
DKK-1是甲羟戊酸途径的一个新靶点，在乳腺癌中被唑来膦酸和阿托伐他汀抑制。
