Metabolic-Pathway-Based Subtyping of Triple-Negative Breast Cancer Reveals Potential Therapeutic Targets

Gong, Yue; Ji, Peng; Yang, Yingju; Xie, Shao Wei; Yu, Tian-Jian; Xiao, Yi; Jin, Ming‐Liang; Ma, Ding; Guo, Lin-Wei; Pei, Yuchen; Chai, Wen-Jun; Li, Da‐Qiang; Bai, Fan; Bertucci, François; Jiang, Yi‐Zhou

doi:10.1016/j.cmet.2020.10.012

Cited by 277 publications

(242 citation statements)

References 74 publications

Supporting

Mentioning

206

Contrasting

Order By: Relevance

“…Metabolic phenotypes of TNBC are different from those of luminal or HER2-enriched BC: cellular metabolism among subtypes of TNBC differs dramatically [ 28 ]. Furthermore, TNBCs can be classified into three metabolic-pathway-based subtypes with distinct metabolic features (the lipogenic subtype with upregulated lipid metabolism, the glycolytic subtype with upregulated carbohydrate and nucleotide metabolism, and the mixed subtype with partial pathway dysregulation) [ 29 ]. Both glycolysis and FA synthesis are essential for cancer cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Down-regulated FST expression is involved in the poor prognosis of triple-negative breast cancer

Liu

Zhao

et al. 2021

Cancer Cell Int

View full text Add to dashboard Cite

Background Triple-negative breast cancer (TNBC) is more commonly associated with young patients, featuring high histological grade, visceral metastasis, and distant recurrence. Follistatin (FST) is a secreted extracellular regulatory protein that antagonizes TGF-β superfamily such as activin and TGF-β related superfamily such as bone morphogenetic protein (BMP). The implication of FST in the proliferation, angiogenesis, and metastasis of solid tumors documents good or poor outcome of patients with BC. However, the role of FST in TNBC remains unclear. Methods Data of 935 patients with breast cancer (BC) were extracted from TCGA. Case–control study, Kaplan–Meier, uni-multivariate COX, and ROC curve were utilized to investigate the relationship between FST expression and the clinical characteristics and prognosis of BC. Functional studies were used to analyze the effect of FST expression on proliferation, apoptosis, migration, and invasion of TNBC cell lines. Bioinformatic methods such as volcanoplot, GO annd KEGG enrichment, and protein–protein interactions (PPI) analyses were conducted to further confirm the different roles of FST in the apoptotic pathways among mesenchymal and mesenchymal stem-like cells of TNBC. Results Data from TCGA showed that low FST expression correlated with poor prognosis (for univariate analysis, HR = 0.47, 95% CI: 0.27–0.82, p = 0.008; for multivariate analysis, HR = 0.40, 95% CI: 0.21–0.75, p = 0.004). Low FST expression provided high predicted value of poor prognosis in TNBC amongst BCs. FST knockdown promoted the proliferation, migration and invasion of BT549 and HS578T cell lines. FST inhibited the apoptosis of mesenchymal cells by targeting BMP7. Conclusions Low FST expression is associated with poor prognosis of patients with TNBC. FST expressions exhibit the anisotropic roles of apoptosis between mesenchymal and mesenchymal stem-like cells but promote the proliferation, migration, invasion in both of two subtypes of TNBC in vitro. FST may be a subtype-heterogeneous biomarker for monitoring the progress of TNBC.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Both glycolysis and FA synthesis are essential for cancer cell proliferation. However, the glycolytic subtype of TNBC is associated with worse outcomes [ 29 ]. Therefore, glycolysis may function as a more important role in the pathogenesis of TNBC than other subtypes of BC.…”

Section: Discussionmentioning

confidence: 99%

Down-regulated FST expression is involved in the poor prognosis of triple-negative breast cancer

Liu

Zhao

et al. 2021

Cancer Cell Int

View full text Add to dashboard Cite

show abstract

“…Thus, new intervention targets and therapeutic strategies are urgently needed for TNBC. TNBCs exhibit several metabolic subtypes some of which are characterized by increased glycolysis [ 37 ], and mitochondrial dysfunction [ 38 ] which may inform therapeutic response and sensitivity to FA withdrawal. The antifolate methotrexate as a single agent in treatment of breast cancer has shown limited efficacy [ 39 ], due at least in part to two common issues with this class of drugs: toxicity and the development of resistance [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

Metabolic Response of Triple-Negative Breast Cancer to Folate Restriction

et al. 2021

View full text Add to dashboard Cite

Background: Triple-negative breast cancers (TNBCs), accounting for approximately 15% of breast cancers, lack targeted therapy. A hallmark of cancer is metabolic reprogramming, with one-carbon metabolism essential to many processes altered in tumor cells, including nucleotide biosynthesis and antioxidant defenses. We reported that folate deficiency via folic acid (FA) withdrawal in several TNBC cell lines results in heterogenous effects on cell growth, metabolic reprogramming, and mitochondrial impairment. To elucidate underlying drivers of TNBC sensitivity to folate stress, we characterized in vivo and in vitro responses to FA restriction in two TNBC models differing in metastatic potential and innate mitochondrial dysfunction. Methods: Metastatic MDA-MB-231 cells (high mitochondrial dysfunction) and nonmetastatic M-Wnt cells (low mitochondrial dysfunction) were orthotopically injected into mice fed diets with either 2 ppm FA (control), 0 ppm FA, or 12 ppm FA (supplementation; in MDA-MB-231 only). Tumor growth, metabolomics, and metabolic gene expression were assessed. MDA-MB-231 and M-Wnt cells were also grown in media with 0 or 2.2 µM FA; metabolic alterations were assessed by extracellular flux analysis, flow cytometry, and qPCR. Results: Relative to control, dietary FA restriction decreased MDA-MB-231 tumor weight and volume, while FA supplementation minimally increased MDA-MB-231 tumor weight. Metabolic studies in vivo and in vitro using MDA-MB-231 cells showed FA restriction remodeled one-carbon metabolism, nucleotide biosynthesis, and glucose metabolism. In contrast to findings in the MDA-MB-231 model, FA restriction in the M-Wnt model, relative to control, led to accelerated tumor growth, minimal metabolic changes, and modest mitochondrial dysfunction. Increased mitochondrial dysfunction in M-Wnt cells, induced via chloramphenicol, significantly enhanced responsiveness to the cytotoxic effects of FA restriction. Conclusions: Given the lack of targeted treatment options for TNBC, uncovering metabolic vulnerabilities that can be exploited as therapeutic targets is an important goal. Our findings suggest that a major driver of TNBC sensitivity to folate restriction is a high innate level of mitochondrial dysfunction, which can increase dependence on one-carbon metabolism. Thus, folate deprivation or antifolate therapy for TNBCs with metabolic inflexibility due to their elevated levels of mitochondrial dysfunction may represent a novel precision-medicine strategy.

show abstract

“…Immune checkpoint inhibitors might be effective for “immune-inflamed” clusters, indicating that these distinct phenotypes were potential biomarkers for predicting therapeutic efficacy. The transformation of “cold tumors” into “hot tumors” should also be considered when dealing with “immune-desert” and “innate immune-inactivated” clusters 73 .…”

Section: Tumor Biomarkersmentioning

confidence: 99%

Progress of Breast Cancer basic research in China

Wang

Guan

et al. 2021

Int. J. Biol. Sci.

View full text Add to dashboard Cite

Breast cancer is the most commonly diagnosed and the most lethal cancer in females both in China and worldwide. Currently, the origin of cancer stem cells, the heterogeneity of cancer cells, the mechanism of cancer metastasis and drug resistance are the most important issues that need to be addressed. Chinese investigators have recently made new discoveries in basic breast cancer researches, especially regarding cancer stem cells, cancer metabolism, and microenvironments. These efforts have led to a deeper understanding of drug resistance and metastasis and have also indicated new biomarkers and therapeutic targets. These findings emphasized the importance of the cancer stem cells for targeted therapy. In this review, we summarized the latest important findings in this field in China.

show abstract

Metabolic-Pathway-Based Subtyping of Triple-Negative Breast Cancer Reveals Potential Therapeutic Targets

Cited by 277 publications

References 74 publications

Down-regulated FST expression is involved in the poor prognosis of triple-negative breast cancer

Down-regulated FST expression is involved in the poor prognosis of triple-negative breast cancer

Metabolic Response of Triple-Negative Breast Cancer to Folate Restriction

Progress of Breast Cancer basic research in China

Contact Info

Product

Resources

About