title: Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis.
abstract: Since bone metastatic breast cancer is an incurable disease, causing significant morbidity and mortality, an understanding of the underlying molecular mechanisms would be highly valuable. Here, we describe in vitro and in vivo evidences for the importance of serine biosynthesis in the metastasis of breast cancer to bone. We first characterized the bone metastatic propensity of the MDA-MB-231(SA) cell line variant as compared to the parental MDA-MB-231 cells by radiographic and histological observations in the inoculated mice. Genome-wide gene expression profiling of this isogenic cell line pair revealed that all the three genes involved in the L: -serine biosynthesis pathway, phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH) were upregulated in the highly metastatic variant. This pathway is the primary endogenous source for L: -serine in mammalian tissues. Consistently, we observed that the proliferation of MDA-MB-231(SA) cells in serine-free conditions was dependent on PSAT1 expression. In addition, we observed that L: -serine is essential for the formation of bone resorbing human osteoclasts and may thus contribute to the vicious cycle of osteolytic bone metastasis. High expression of PHGDH and PSAT1 in primary breast cancer was significantly associated with decreased relapse-free and overall survival of patients and malignant phenotypic features of breast cancer. In conclusion, high expression of serine biosynthesis genes in metastatic breast cancer cells and the stimulating effect of L: -serine on osteoclastogenesis and cancer cell proliferation indicate a functionally critical role for serine biosynthesis in bone metastatic breast cancer and thereby an opportunity for targeted therapeutic interventions.
authors.affiliation: Medical Biotechnology, VTT Technical Research Center of Finland and Turku Center for Biotechnology, Turku, Finland ext-sirkku.pollari@vtt.fi
authors.forename: Sirkku
authors.initials: S
authors.lastname: Pollari
authors.forename: Sanna-Maria
authors.initials: SM
authors.lastname: Käkönen
authors.forename: Henrik
authors.initials: H
authors.lastname: Edgren
authors.forename: Maija
authors.initials: M
authors.lastname: Wolf
authors.forename: Pekka
authors.initials: P
authors.lastname: Kohonen
authors.forename: Henri
authors.initials: H
authors.lastname: Sara
authors.forename: Theresa
authors.initials: T
authors.lastname: Guise
authors.forename: Matthias
authors.initials: M
authors.lastname: Nees
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary*; D001862:Bone Resorption; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D051379:Mice; D009368:Neoplasm Transplantation; D010010:Osteoclasts / Q000502:physiology*; D050543:Phosphoglycerate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D012694:Serine / Q000096:biosynthesis* / Q000494:pharmacology; D015996:Survival Rate; D000637:Transaminases / Q000235:genetics / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D012694:Serine; D050543:Phosphoglycerate Dehydrogenase; D000637:Transaminases; C022393:phosphoserine aminotransferase; D010744:Phosphoric Monoester Hydrolases; C022394:phosphoserine phosphatase