Triple negative breast cancer (TNBC) is a deadly form of breast cancer due to the development of resistance to chemotherapy affecting over 30% of patients. New therapeutics and companion biomarkers are urgently needed. Recognizing the elevated expression of glucose transporter 1 (GLUT1, encoded by SLC2A1 ) and associated metabolic dependencies in TNBC, we investigated the vulnerability of TNBC cell lines and patient-derived samples to GLUT1 inhibition. We report that genetic or pharmacological inhibition of GLUT1 with BAY-876 impairs the growth of a subset of TNBC cells displaying high glycolytic and lower oxidative phosphorylation (OXPHOS) rates. Pathway enrichment analysis of gene expression data suggests that the functionality of the E2F pathway may reflect to some extent OXPHOS activity. Furthermore, the protein levels of retinoblastoma tumor suppressor (RB1) strongly correlate with the degree of sensitivity to GLUT1 inhibition in TNBC, where RB1-negative cells are insensitive to GLUT1 inhibition. Collectively, our results highlight a strong and targetable RB1-GLUT1 metabolic axis in TNBC and warrant clinical evaluation of GLUT1 inhibition in TNBC patients stratified according to RB1 protein expression levels.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the worst prognosis and few effective therapies. Here we identified MS023, an inhibitor of type I protein arginine methyltransferases (PRMTs), which has antitumor growth activity in TNBC. Pathway analysis of TNBC cell lines indicates that the activation of interferon responses before and after MS023 treatment is a functional biomarker and determinant of response, and these observations extend to a panel of human-derived organoids. Inhibition of type I PRMT triggers an interferon response through the antiviral defense pathway with the induction of double-stranded RNA, which is derived, at least in part, from inverted repeat Alu elements. Together, our results represent a shift in understanding the antitumor mechanism of type I PRMT inhibitors and provide a rationale and biomarker approach for the clinical development of type I PRMT inhibitors.

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Intervertebral disc degeneration (IVDD) is a major health problem. Although mesenchymal stem cells (MSCs) have been used to promote IVD regeneration, the actual survival time of implanted MSCs in IVDs has never been studied noninvasively and continuously in vivo. To investigate survival of implanted MSCs in vivo, this study used a canine model of degenerated IVD and MSCs transfected with a mutant herpes simplex type-1 virus thymidine kinase and labeled with magnetic iron oxide nanoparticles (MION). One-stage positron emission tomography (PET) and magnetic resonance (MR) imaging were carried out 3 days and 2 weeks, 3 weeks, and 4 weeks after implantation of MSCs into IVDs with surgically induced degeneration. Pfirrmann disc degeneration grade determined from the MR images indicated that the repair progress of degenerated IVD stopped 3 weeks after MSC implantation. Meanwhile, MION signal strength, signal contrast ratio (%), and low signal area (mm) did not change significantly from that seen 3 days after cell implantation until 4 weeks [751.43 (4 weeks) ±52.67 (3 days) vs. 225.34 ± 35.62; 47.37 ± 5.01 vs. 85.37 ± 10.54; 1.78 ± 0.31 vs. 5.29 ± 1.35; P < 0.01, respectively]. Accumulation of the PET reporter probe, 9-(4-[F]-fluoro-3-hydroxymethylbutyl)-guanine, was dramatically decreased at 3 weeks after MSC implantation. These results demonstrated that MSCs could survive no more than 3 weeks after implantation into IVDs with surgically induced degeneration, suggesting that MSCs could contribute to IVD repair for the first 3 weeks after implantation. The results also indicate that PET imaging could be used reliably to quantify the survival of implanted MSCs, whereas MION with MR imaging would likely be unsuitable for long-term tracking of MSCs in IVDs.

Studies investigating the association between glutathione S-transferase M1 (GSTM1) polymorphism and bladder cancer risk report conflicting results. The objective of this study was to quantitatively summarize the evidence for such a relationship. We performed a systematic search of the National Library of Medline and Embase databases. This meta-analysis included 26 case-control studies, which included 5029 bladder cancer cases and 6680 controls. The combined results based on all studies showed that the GSTM1 null genotype was associated with an increased risk of bladder cancer (OR=1.46, 95% confidence interval [CI]=1.35, 1.57). When stratifying for race, results were similar among Asians (OR=1.60, 95% CI=1.27, 2.01) and Caucasians (OR=1.44, 95% CI=1.33, 1.57) except Africans (OR=1.25, 95% CI=0.76, 2.06). When stratifying by the smoking, stage, grade, and histological type of bladder cancer, we found no statistical association. Our meta-analysis suggests that the GSTM1 null genotype is associated with a modest increase in the risk of bladder cancer.

No abstract

Triple negative breast cancer (TNBC) is a deadly form of breast cancer due to the development of resistance to chemotherapy affecting over 30% of patients. New therapeutics and companion biomarkers are urgently needed. Recognizing the elevated expression of glucose transporter 1 (GLUT1, encoded by SLC2A1) and associated metabolic dependencies in TNBC, we investigated the vulnerability of TNBC cell lines and patient-derived samples to GLUT1 inhibition. We report that genetic or pharmacological inhibition of GLUT1 with BAY-876 impairs the growth of a subset of TNBC cells displaying high glycolytic and lower oxidative phosphorylation (OXPHOS) rates. Pathway enrichment analysis of gene expression data implicates E2F Targets pathway activity as a surrogate of OXPHOS activity. Furthermore, the protein levels of retinoblastoma tumor suppressor (RB1) are strongly correlated with the degree of sensitivity to GLUT1 inhibition in TNBC, where RB1-negative cells are insensitive to GLUT1 inhibition. Collectively, our results highlight a strong and targetable RB1-GLUT1 metabolic axis in TNBC and warrant clinical evaluation of GLUT1 inhibition in TNBC patients stratified according to RB1 protein expression levels.

No abstract