title: TGFβ-Mediated induction of SphK1 as a potential determinant in human MDA-MB-231 breast cancer cell bone metastasis.
abstract: Mechanistic understanding of the preferential homing of circulating tumor cells to bone and their perturbation on bone metabolism within the tumor-bone microenvironment remains poorly understood. Alteration in both transforming growth factor β (TGFβ) signaling and sphingolipid metabolism results in the promotion of tumor growth and metastasis. Previous studies using MDA-MB-231 human breast cancer-derived cell lines of variable metastatic potential were queried for changes in sphingolipid metabolism genes to explore correlations between TGFβ dependence and bone metastatic behavior. Of these genes, only sphingosine kinase-1 (SPHK1) was identified to be significantly increased following TGFβ treatment. Induction of SPHK1 expression correlated to the degree of metastatic capacity in these MDA-MB-231-derived cell lines. We demonstrate that TGFβ mediates the regulation of SPHK1 gene expression, protein kinase activity and is critical to MDA-MB-231 cell viability. Furthermore, a bioinformatic analysis of human breast cancer gene expression supports SPHK1 as a hallmark TGFβ target gene that also bears the genetic fingerprint of the basal-like/triple-negative breast cancer molecular subtype. These data suggest a potential new signaling axis between TGFβ/SphK1 that may have a role in the development, prognosis or the clinical phenotype associated with tumor-bone metastasis.
authors.affiliation: Department of Pharmacology, Indiana University School of Medicine , Indianapolis, IN, USA ; Lilly Research Laboratories, Eli Lilly & Company , Indianapolis, IN, USA.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Stayrook
authors.affiliation: Lilly Research Laboratories, Eli Lilly & Company , Indianapolis, IN, USA.
authors.forename: Justin K
authors.initials: JK
authors.lastname: Mack
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine , Indianapolis, IN, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Cerabona
authors.affiliation: Lilly Research Laboratories, Eli Lilly & Company , Indianapolis, IN, USA.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Edwards
authors.affiliation: Lilly Research Laboratories, Eli Lilly & Company , Indianapolis, IN, USA.
authors.forename: Hai H
authors.initials: HH
authors.lastname: Bui
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Indiana University-Purdue University at Indianapolis , Indianapolis, IN, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Niewolna
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Indiana University-Purdue University at Indianapolis , Indianapolis, IN, USA.
authors.forename: Pierrick Gj
authors.initials: PG
authors.lastname: Fournier
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Indiana University-Purdue University at Indianapolis , Indianapolis, IN, USA.
authors.forename: Khalid S
authors.initials: KS
authors.lastname: Mohammad
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Indiana University-Purdue University at Indianapolis , Indianapolis, IN, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Waning
authors.affiliation: Department of Pharmacology, Indiana University School of Medicine , Indianapolis, IN, USA ; Division of Endocrinology and Metabolism, Department of Medicine, Indiana University-Purdue University at Indianapolis , Indianapolis, IN, USA.
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Guise