Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis
Open accessAbstract
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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High levels of PHGDH protein expression relative to normal tissue correlate with disease severity in breast cancer patients.
“High levels of PHGDH protein expression relative to normal tissue correlates with disease severity in breast cancer patients (Pollari et al., 2011).”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Pollari et al., 2011
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Self-citation
- Authors
- Pollari, S., Käkönen, S.-M., Edgren, H., Wolf, M., Kohonen, P., Sara, H., Guise, T., Nees, M., & Kallioniemi, O.
- Affiliations
- Turku Centre for Biotechnology (FI)
- University of Turku (FI)
- University of Helsinki (FI)
- Indiana University Indianapolis (US)
- Corresponding author
- Pollari, Sirkku
- ORCID
- Venue
- Breast Cancer Research and Treatment
- Published
- 2010-03-30
- Volume
- 125
- Issue
- 2
- Pages
- 421-430
- ISSN
- 0167-6806 (ISSN-L)
- 1573-7217
- OpenAlex
- W2014460958
- Cited by
- 269
- References
- 27
- Citations by year
- 2026: 6 · 2025: 16 · 2024: 18 · 2023: 17 · 2022: 23 · 2021: 25 · 2020: 21 · 2019: 22 · 2018: 21 · 2017: 15 · 2016: 12 · 2015: 16 · 2014: 10 · 2013: 11 · 2012: 18
- FWCI
- 4.73
- Type
- journal article
- Language
- en
- Open access
- green
- hal.science
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Breast Cancer Research and Treatment (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Työväentutkimus Vuosikirja (submittedVersion, other-oa)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
- Funders
- National Cancer Institute (R01CA069158, R01 CA 69158)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Keywords
- serine biosynthesis, breast cancer bone metastasis, osteoclastogenesis, L-serine, PHGDH, PSAT1, phosphoserine phosphatase, osteolytic bone metastasis, tumor cell proliferation, gene expression profiling, patient survival
- MeSH terms
- Transaminases, Animals, Bone Neoplasms, Bone Resorption, Breast Neoplasms, Cell Differentiation, Female, Humans, Mammary Neoplasms, Experimental, Neoplasm Transplantation, Osteoclasts, Phosphoric Monoester Hydrolases, Serine, Blotting, Western, Survival Rate, Polymerase Chain Reaction, Gene Expression Profiling, RNA, Small Interfering, Cell Line, Tumor, Cell Proliferation, Phosphoglycerate Dehydrogenase, Mice
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