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.
Highlights
Amino-bisphosphonates and statins inhibit the mevalonate pathway, and may exert anti-tumor effects
Dickkopf-1 expression is suppressed by zoledronic acid and atorvastatin in breast cancer cell lines in vitro To identify novel targets of zoledronic acid, a Wnt signaling pathway polymerase chain reaction (PCR) array was conducted with MDA-231 breast cancer cells after 24 hours of treatment with zoledronic acid
Additional file 1: Figure S1. (A) results from a Wnt signaling pathway PCR array conducted with MDA-231 breast cancer cells after 24 hours of treatment with zoledronic acid
Summary
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. DKK-1 expression increases in early stages while decreasing during progression towards metastatic disease [17]. These data indicate that DKK-1 may have a pathophysiological role in skeletal metastases of breast and prostate cancer. We identified DKK-1 as a novel target of the mevalonate pathway in estrogen receptor (ER)negative breast cancer that can be modulated by BPs and statins via inhibiting of geranylgeranylation
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