Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis

Sirkku Pollari (Corresponding Author), Sanna-Maria Käkönen, Henrik Edgren, Maija Wolf, Pekka Kohonen, Henri Sara, Theresa Guise, Matthias Nees, Olli Kallioniemi

Research output: Contribution to journalArticleScientificpeer-review

114 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)421-430
JournalBreast Cancer Research and Treatment
Volume125
Issue number2
DOIs
Publication statusPublished - 2011
MoE publication typeA1 Journal article-refereed

Fingerprint

Osteogenesis
Serine
phosphoserine aminotransferase
Breast Neoplasms
Bone and Bones
Phosphoglycerate Dehydrogenase
Neoplasm Metastasis
Cell Line
Bone Neoplasms
Gene Expression Profiling
Osteoclasts
Genes
Cell Proliferation
Genome
Morbidity
Recurrence
Survival
Mortality
Neoplasms

Keywords

  • Breast cancer
  • Bone metastasis
  • Osteoclast
  • l-serine

Cite this

Pollari, S., Käkönen, S-M., Edgren, H., Wolf, M., Kohonen, P., Sara, H., ... Kallioniemi, O. (2011). Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis. Breast Cancer Research and Treatment, 125(2), 421-430. https://doi.org/10.1007/s10549-010-0848-5
Pollari, Sirkku ; Käkönen, Sanna-Maria ; Edgren, Henrik ; Wolf, Maija ; Kohonen, Pekka ; Sara, Henri ; Guise, Theresa ; Nees, Matthias ; Kallioniemi, Olli. / Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis. In: Breast Cancer Research and Treatment. 2011 ; Vol. 125, No. 2. pp. 421-430.
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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.",
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Pollari, S, Käkönen, S-M, Edgren, H, Wolf, M, Kohonen, P, Sara, H, Guise, T, Nees, M & Kallioniemi, O 2011, 'Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis', Breast Cancer Research and Treatment, vol. 125, no. 2, pp. 421-430. https://doi.org/10.1007/s10549-010-0848-5

Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis. / Pollari, Sirkku (Corresponding Author); Käkönen, Sanna-Maria; Edgren, Henrik; Wolf, Maija; Kohonen, Pekka; Sara, Henri; Guise, Theresa; Nees, Matthias; Kallioniemi, Olli.

In: Breast Cancer Research and Treatment, Vol. 125, No. 2, 2011, p. 421-430.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis

AU - Pollari, Sirkku

AU - Käkönen, Sanna-Maria

AU - Edgren, Henrik

AU - Wolf, Maija

AU - Kohonen, Pekka

AU - Sara, Henri

AU - Guise, Theresa

AU - Nees, Matthias

AU - Kallioniemi, Olli

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

KW - Breast cancer

KW - Bone metastasis

KW - Osteoclast

KW - l-serine

U2 - 10.1007/s10549-010-0848-5

DO - 10.1007/s10549-010-0848-5

M3 - Article

VL - 125

SP - 421

EP - 430

JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

SN - 0167-6806

IS - 2

ER -