title: SDPR functions as a metastasis suppressor in breast cancer by promoting apoptosis.
abstract: Metastatic dissemination of breast cancer cells represents a significant clinical obstacle to curative therapy. The loss of function of metastasis suppressor genes is a major rate-limiting step in breast cancer progression that prevents the formation of new colonies at distal sites. However, the discovery of new metastasis suppressor genes in breast cancer using genomic efforts has been slow, potentially due to their primary regulation by epigenetic mechanisms. Here, we report the use of model cell lines with the same genetic lineage for the identification of a novel metastasis suppressor gene, serum deprivation response (SDPR), localized to 2q32-33, a region reported to be associated with significant loss of heterozygosity in breast cancer. In silico metaanalysis of publicly available gene expression datasets suggests that the loss of expression of SDPR correlates with significantly reduced distant-metastasis-free and relapse-free survival of breast cancer patients who underwent therapy. Furthermore, we found that stable SDPR overexpression in highly metastatic breast cancer model cell lines inhibited prosurvival pathways, shifted the balance of Bcl-2 family proteins in favor of apoptosis, and decreased migration and intravasation/extravasation potential, with a corresponding drastic suppression of metastatic nodule formation in the lungs of NOD/SCID mice. Moreover, SDPR expression is silenced by promoter DNA methylation, and as such it exemplifies epigenetic regulation of metastatic breast cancer progression. These observations highlight SDPR as a potential prognostic biomarker and a target for future therapeutic applications.
authors.affiliation: Cell and Molecular Biology Graduate Program, Boston University School of Medicine, Boston, MA 02118; Molecular and Translational Medicine Graduate Program, Department of Medicine, Boston University School of Medicine, Boston, MA 02118; Biomedical Genetics Section and Cancer Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118;
authors.forename: Sait
authors.initials: S
authors.lastname: Ozturk
authors.affiliation: Biomedical Genetics Section and Cancer Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118; Genetics and Genomics Graduate Program, Boston University School of Medicine, Boston, MA 02118;
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Papageorgis
authors.affiliation: Biomedical Genetics Section and Cancer Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118; Genetics and Genomics Graduate Program, Boston University School of Medicine, Boston, MA 02118;
authors.forename: Chen Khuan
authors.initials: CK
authors.lastname: Wong
authors.affiliation: Molecular and Translational Medicine Graduate Program, Department of Medicine, Boston University School of Medicine, Boston, MA 02118; Biomedical Genetics Section and Cancer Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118;
authors.forename: Arthur W
authors.initials: AW
authors.lastname: Lambert
authors.affiliation: Biomedical Genetics Section and Cancer Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118;
authors.forename: Hamid M
authors.initials: HM
authors.lastname: Abdolmaleky
authors.affiliation: Biomedical Genetics Section and Cancer Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118;
authors.forename: Arunthathi
authors.initials: A
authors.lastname: Thiagalingam
authors.affiliation: Cell and Molecular Biology Graduate Program, Boston University School of Medicine, Boston, MA 02118; Molecular and Translational Medicine Graduate Program, Department of Medicine, Boston University School of Medicine, Boston, MA 02118; Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118.
authors.forename: Herbert T
authors.initials: HT
authors.lastname: Cohen
authors.affiliation: Cell and Molecular Biology Graduate Program, Boston University School of Medicine, Boston, MA 02118; Molecular and Translational Medicine Graduate Program, Department of Medicine, Boston University School of Medicine, Boston, MA 02118; Biomedical Genetics Section and Cancer Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118; Genetics and Genomics Graduate Program, Boston University School of Medicine, Boston, MA 02118; Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118 samthia@bu.edu.
authors.forename: Sam
authors.initials: S
authors.lastname: Thiagalingam
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D016688:Mice, Inbred NOD; D028044:Phosphate-Binding Proteins
chemical_list: C112303:CAVIN2 protein, human; D002352:Carrier Proteins; D028044:Phosphate-Binding Proteins
keywords: SDPR; breast cancer; epigenetics; metastasis; metastasis suppressor