Regulation of SVEP1 gene expression by 17β-estradiol and TNFα in pre-osteoblastic and mammary adenocarcinoma cells

Breast cancer is one of several tumors, including prostate, thyroid and kidney, which display a remarkable predilection for metastasis to bone. The preference to metastasize to bone by tumor cells relies on specific interactions among tumor cells, bone marrow microenvironment and bone cells. Osteomimicry is postulated to enable the survival of tumor cells in the bone tissue. Using gene profiling array and RT-PCR we demonstrated the message expression of few bone matrix proteins in mammary adenocarcinoma cells as well as that of cell adhesion molecules (CAMs). A CAM molecule, named SVEP1, was previously shown to be expressed in osteoblastic cells both in vivo and in vitro mediating cell adhesion in the bone-marrow niches. Both estradiol (17βE2) and TNFα regulate the expression of adhesion molecules and act in bone-cancer-crosstalk. We focused on differential regulation of SVEP1 gene comparing pre-osteoblastic MBA-15 and mammary adenocarcinoma DA3 cells. 17βE2 and TNFα activated SVEP1 promoter, increased its message and protein levels in both cell types. Using chromatin immunoprecipitation assay, we quantified SVEP1 promoter occupancy by transcription factors; TFIIB, ERα, NF-κB, Sp1 and their binding was also regulated by both factors. By comparing pre-osteoblastic with mammary adenocarcinoma cells, the study expands our understanding of SVEP1 gene expression regulation and it sheds light on its involvement in bone-cancer-microenvironment interactions.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Osteomimicry may enable survival of tumor cells in the bone tissue. ► We model two cell lines: pre-osteoblasts and mammary adenocarcinoma. ► SVEP1 is a cell adhesion molecule that mediates cellular adhesion in bone-marrow niches. ► SVEP1 mRNA expression is regulated by estradiol and TNFα. ► Specific transcription factors bind to SVEP1 promoter thereby regulate its activity. ► The study sheds light on SVEP1 transcription in the bone-cancer-microenvironment.