Bone Abstracts

Metastasis to bone is the leading cause of death for breast carcinoma, and much focus in the biology and therapy relays on epigenetic alterations. Since DNA-methyltransferase blockade counteracts tumour growth, we utilized 5-aza-2′-deoxycytidine (dAza) to clarify whether molecular events undergoing epigenetic control were critical for bone metastatization. Here, we studied Secreted-Protein Acidic and Rich in Cysteine (SPARC), matricellular glycoprotein associated with bone-remodelling, and Endothelin1 (ET1), important for osteomimetic properties of metastatic cells, to test the hypothesis that DNA methylation in bone metastasis orchestrated a coordinate function of SPARC and ET1. In the xenograft model, prepared with 1833 clone derived from MDA-MB231-human breast carcinoma cells, we showed strong signals for SPARC and ET1. dAza administration slowed-down metastasis outgrowth, possibly consequent to SPARC and ET1 reductions at invasive front and in the bone marrow, mostly due to loss of Twist. In metastasis bulk, Snail was partly reduced by dAza, sustaining ET1-SPARC cooperativity. In 1833 cells, ET1 Induced SPARC, and both underwent post-translational control by miRNAs: ectopic miR29a reduced SPARC expression, while ET1 down-regulation occurred in the presence of endogenous-miR98 expression. Consistently, in human specimens from patients with breast carcinoma metastasizing to bone, SPARC and ET1/ET1 receptor A (ET_AR) axis were highly expressed in dysplasia and bone metastatic cells and stroma, but not in the stroma of pair-matched primary invasive ductal carcinoma. The early identification of SPARC/ET1/ET_AR in dysplastic lesions has a prognostic value to devise therapies against metastasis engraftment. We hypothesize that local production of SPARC in the hospitable bone, possibly regulated by ET1/ET_AR axis, would be important for bone niche formation and evolution. Thus, the blockade of DNA methyltransferases leading to SPARC reduction in vivo, might represent a promising strategy to hamper early steps of the metastatic process affecting the osteogenic niche.