Metabolic Profiling Reveals a Dependency of Human Metastatic Breast Cancer on Mitochondrial Serine and One-Carbon Unit Metabolism.

TitleMetabolic Profiling Reveals a Dependency of Human Metastatic Breast Cancer on Mitochondrial Serine and One-Carbon Unit Metabolism.
Publication TypeJournal Article
Year of Publication2020
AuthorsLi, AM, Ducker, GS, Li, Y, Seoane, JA, Xiao, Y, Melemenidis, S, Zhou, Y, Liu, L, Vanharanta, S, Graves, EE, Rankin, EB, Curtis, C, Massagué, J, Rabinowitz, JD, Thompson, CB, Ye, J
JournalMol Cancer Res
Volume18
Issue4
Pagination599-611
Date Published2020 04
ISSN1557-3125
Abstract

<p>Breast cancer is the most common cancer among American women and a major cause of mortality. To identify metabolic pathways as potential targets to treat metastatic breast cancer, we performed metabolomics profiling on the breast cancer cell line MDA-MB-231 and its tissue-tropic metastatic subclones. Here, we report that these subclones with increased metastatic potential display an altered metabolic profile compared with the parental population. In particular, the mitochondrial serine and one-carbon (1C) unit pathway is upregulated in metastatic subclones. Mechanistically, the mitochondrial serine and 1C unit pathway drives the faster proliferation of subclones through enhanced purine biosynthesis. Inhibition of the first rate-limiting enzyme of the mitochondrial serine and 1C unit pathway, serine hydroxymethyltransferase (SHMT2), potently suppresses proliferation of metastatic subclones in culture and impairs growth of lung metastatic subclones at both primary and metastatic sites in mice. Some human breast cancers exhibit a significant association between the expression of genes in the mitochondrial serine and 1C unit pathway with disease outcome and higher expression of SHMT2 in metastatic tumor tissue compared with primary tumors. In addition to breast cancer, a few other cancer types, such as adrenocortical carcinoma and kidney chromophobe cell carcinoma, also display increased SHMT2 expression during disease progression. Together, these results suggest that mitochondrial serine and 1C unit metabolism plays an important role in promoting cancer progression, particularly in late-stage cancer. IMPLICATIONS: This study identifies mitochondrial serine and 1C unit metabolism as an important pathway during the progression of a subset of human breast cancers.</p>

DOI10.1158/1541-7786.MCR-19-0606
Alternate JournalMol. Cancer Res.
PubMed ID31941752
PubMed Central IDPMC7127984
Grant ListT32 CA009302 / CA / NCI NIH HHS / United States
MC_UU_12022/7 / MRC_ / Medical Research Council / United Kingdom
MC_UP_1101/4 / MRC_ / Medical Research Council / United Kingdom
K99 CA184239 / CA / NCI NIH HHS / United States
R00 CA184239 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
K99 CA215307 / CA / NCI NIH HHS / United States