bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2024–11–03
six papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. DLAT promotes triple-negative breast cancer progression via YAP1 activation.
  2. ACSS2 regulates ferroptosis in an E2F1-dependent manner in breast cancer brain metastatic cells.
  3. PRODH Regulates Tamoxifen Resistance through Ferroptosis in Breast Cancer Cells.
  4. Effect of genistein supplementation on microenvironment regulation of breast tumors in obese mice.
  5. Overexpression of SLAP2 inhibits triple-negative breast cancer progression by promoting macrophage M1-type polarization.
  6. Gluconeogenesis and glycogenolysis required in metastatic breast cancer cells.
  1. Cancer Biol Ther. 2024 Dec 31. 25(1): 2421578
    DLAT promotes triple-negative breast cancer progression via YAP1 activation.
    Diya Liu, Xuehui Wang, Fengyuan Qian, Danrong Ye, Xiaochong Deng, Lin Fang.
       BACKGROUND: Breast cancer (BC) is the most prevalent malignant tumor in women globally. Triple-negative breast cancer (TNBC) represents the most malignant and invasive subtype of BC. New therapeutic targets are urgently needed for TNBC owing to its receptor expression characteristics, which render it insensitive to traditional targeted and endocrine therapies for BC. The role and mechanisms of dihydrolipoamide S-acetyltransferase (DLAT) as a crucial molecule in glycometabolism and cuproptosis-related biological processes in tumors remain to be explored.
    METHODS: DLAT expression was investigated using bioinformatics methods and quantitative real-time polymerase chain reaction. Subsequently, the MTT assay, colony formation assay, and migration-invasion assay were performed to validate the effect of DLAT on TNBC cell viability, proliferation, and migration. Cytoplasmic-nuclear separation experiments, western blot analysis, and co-immunoprecipitation assays were performed to elucidate the underlying molecular mechanisms.
    RESULTS: This study revealed a robust correlation between elevated DLAT expression in BC and unfavorable prognosis in patients, with higher expression of DLAT compared to other subtypes in TNBC. Functional cytology experiments indicated that DLAT plays a tumor-promoting role in TNBC. Mechanistic studies showed that DLAT directly interacts with YAP1, leading to the dephosphorylation and activation of YAP1 and its increased nuclear translocation, thereby transcriptionally activating and regulating downstream oncogenes, promoting the malignant phenotype of TNBC. Rescue experiments indicated that DLAT promotes the malignant behavior of TNBC through a YAP1-dependent pathway.
    CONCLUSIONS: Our research unveiled the significant involvement of DLAT in TNBC, along with the potential for modulating DLAT/YAP1 activity as a targeted treatment strategy for TNBC.
    Keywords:  Breast cancer; DLAT; YAP1; triple-negative breast cancer; tumor progression
    DOI:  https://doi.org/10.1080/15384047.2024.2421578
  2. bioRxiv. 2024 Oct 21. pii: 2024.10.18.619082. [Epub ahead of print]
    ACSS2 regulates ferroptosis in an E2F1-dependent manner in breast cancer brain metastatic cells.
    Emily M Esquea, Riley G Young, Lorela Ciraku, Jessica Merzy, Nusaiba N Ahmed, Alexandra N Talarico, Mangalam Karuppiah, Wiktoria Gocal, Nicole L Simone, Alexej Dick, Mauricio J Reginato.
      Brain metastasis diagnosis in breast cancer patients is considered an end-stage event. The median survival after diagnosis is measured in months, thus there is an urgent need to develop novel treatment strategies. Breast cancers that metastasize to the brain must adapt to the unique brain environment and are highly dependent on acetate metabolism for growth and survival. However, the signaling pathways that regulate survival in breast cancer brain metastatic (BCBM) tumors are not known. Primary brain tumor cells can convert acetate to acetyl-CoA via phosphorylation of acetyl-CoA synthetase 2 (ACSS2) by the cyclin-dependent kinase-5 (CDK5) regulated by the nutrient sensor O-GlcNAc transferase (OGT). Here, we show that breast cancer cells selected to metastasize to the brain contain increased levels of O-GlcNAc, OGT and ACSS2-Ser267 phosphorylation compared to parental breast cancer cells. Moreover, OGT and CDK5 are required for breast cancer cell growth in the brain parenchyma in vivo. Importantly, ACSS2 and ACSS2-S267D phospho-mimetic mutant are critical for in vivo breast cancer growth in the brain but not in the mammary fat pad. Mechanistically, we show that ACSS2 regulates BCBM cell survival by suppressing ferroptosis via regulation of E2F1-mediated expression of anti-ferroptotic proteins SLC7A11 and GPX4. Lastly, we show treatment with a novel brain-permeable small molecule ACSS2 inhibitor induced ferroptosis and reduced BCBM growth ex vivo and in vivo . These results suggest a crucial role for ACSS2 in protecting from ferroptosis in breast cancer brain metastatic cells and suggests that breast cancer brain metastatic cells may be susceptible to ferroptotic inducers.
    DOI:  https://doi.org/10.1101/2024.10.18.619082
  3. Genes (Basel). 2024 Oct 14. pii: 1316. [Epub ahead of print]15(10):
    PRODH Regulates Tamoxifen Resistance through Ferroptosis in Breast Cancer Cells.
    Ping Zhang, Na Qian, Haigen Lai, Shu Chen, Kuaiying Wu, Xiaofeng Luo, Bo Lei, Mengqi Liu, Jiajun Cui.
       BACKGROUND: Estrogen receptor-positive breast cancer accounts for around 70% of all cases. Tamoxifen, an anti-estrogenic inhibitor, is the primary drug used for this type of breast cancer treatment. However, tamoxifen resistance is a major challenge in clinics. Metabolic reprogramming, an emerging hallmark of cancer, plays a key role in cancer initiation, progression, and therapy resistance. The metabolism of non-essential amino acids such as serine, proline, and glutamine is involved in tumor metabolism reprogramming. Although the association of glutamine metabolism with tamoxifen resistance has been well established, the role of proline metabolism and its critical enzyme PRODH is unknown.
    OBJECTIVE: The aim of this study is to explore the role and mechanism of PRODH in tamoxifen resistance in breast cancer cells.
    METHODS: PRODH and GPX4 expressions in tamoxifen-resistant cells were detected using real-time PCR and Western blot analysis. The breast cells' response to tamoxifen was measured using MTT assays. Trans-well assays were used to detect cell migration and invasion. A Xenograft tumor assay was used to detect the role of PRODH in tumor growth. Reactive oxygen species were measured using flow cytometry.
    RESULTS: PRODH expression is reduced in tamoxifen-resistant cells, and its overexpression enhances tamoxifen response in vitro and in vivo. Conversely, PRODH knockdown confers tamoxifen resistance in tamoxifen-sensitive cells. Mechanistic studies show that ferroptosis is inhibited in tamoxifen-resistant cells and overexpression of PRODH restores the ferroptosis in tamoxifen-resistant cells. Moreover, Ferrostatin-1 (Fer-1), the ferroptosis inhibitor, reversed the effect of PRODH on tamoxifen resistance.
    CONCLUSIONS: These findings suggest that PRODH regulates tamoxifen resistance by regulating ferroptosis in tamoxifen-resistant cells.
    Keywords:  PRODH; ferroptosis; proline; tamoxifen resistance
    DOI:  https://doi.org/10.3390/genes15101316
  4. Breast Cancer Res. 2024 Oct 25. 26(1): 147
    Effect of genistein supplementation on microenvironment regulation of breast tumors in obese mice.
    Shengzi Jin, Yingce Zheng, Ding Li, Xingyao Liu, Tingting Zhu, Shuang Wang, Zhonghua Liu, Yun Liu.
      Obesity is an important risk factor for breast cancer in women before and after menopause. Adipocytes, key mediators in the tumor microenvironment, play a pivotal role in the relationship between obesity with cancer. However, the potential of dietary components in modulating this relationship remains underexplored. Genistein, a soy-derived isoflavone, has shown promise in reducing breast cancer risk, attenuating obesity-associated inflammation, and improving insulin resistance. However, there are no reports examining whether genistein has the ability to reduce the effects of obesity on breast tumor development. In this study, we constructed a mammary tumor model in ovariectomized obese mice and examined the effects of genistein on body condition and tumor growth. Moreover, the effects of genistein on the tumor microenvironment were examined via experimental observation of peritumoral adipocytes and macrophages. In addition, we further investigated the effect of genistein on adipocyte and breast cancer cell crosstalk via coculture experiments. Our findings indicate that dietary genistein significantly alleviates obesity, systemic inflammation, and metabolic disorders induced by a high-fat diet in ovariectomized mice. Notably, it also inhibits tumor growth in vivo. The impact of genistein extends to the tumor microenvironment, where it reduces the production of cancer-associated adipocytes (CAAs) and the recruitment of M2d-subtype macrophages. In vitro, genistein mitigates the transition of adipocytes into CAAs and inhibits the expression of inflammatory factors by activating PPAR-γ pathway and degrading nuclear NF-κB. Furthermore, it impedes the acquisition of invasive properties and epithelial‒mesenchymal transition in breast cancer cells under CAA-induced inflammation, disrupting the Wnt3a/β-catenin pathway. Intriguingly, the PPAR-γ inhibitor T0070907 counteracted the effects of genistein in the coculture system, underscoring the specificity of its action. Our study revealed that genistein can mitigate the adverse effects of obesity on breast cancer by modulating the tumor microenvironment. These findings provide new insights into how genistein intake and a soy-based diet can reduce breast cancer risk.
    Keywords:  Breast cancer; Cancer associated adipocyte; Genistein; Obesity; PPAR-γ; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13058-024-01904-8
  5. Sci Rep. 2024 10 29. 14(1): 26035
    Overexpression of SLAP2 inhibits triple-negative breast cancer progression by promoting macrophage M1-type polarization.
    Shun Wu, Fang Guo, Manxiu Li, Wei Chen, Liting Jin.
      Breast cancer is the most common malignant tumor in women, and triple-negative breast cancer (TNBC) is a specific subtype of breast cancer characterized by high invasiveness, high metastatic potential, ease of recurrence, and poor prognosis. Src-like adaptor protein 2 (SLAP2), which can be involved in the regulation of multiple signaling pathways, may be a key target for TNBC. The aim of this study was to investigate the effect of overexpression of SLAP2 on TNBC and to explore the underlying mechanisms. First, we constructed and transfected SLAP2 overexpressing lentivirus based on MDA-MB-231 human TNBC cell line, screened for differential downstream target genes in combination with mRNA high-throughput sequencing (RNA-Seq), and predicted their functions and enriched pathways in conjunction with bioinformatics analysis. The effects of SLAP2 overexpression on macrophage polarization, as well as on tumor proliferation and apoptosis, were assessed by tail vein injection of a stable transfection line of 4T1 cells transfected with SLAP2 overexpressing lentivirus. The effect of SLAP2 on macrophage polarization was assessed by inducing M1/M2 polarization and transfecting SLAP2 overexpressing lentivirus. Meanwhile, a transwell co-culture system was constructed between differently treated macrophages and 4T1 cells to assess the effect of SLAP2 overexpression on the malignant behavior of the cells via macrophage polarization. Overexpression of SLAP2 revealed 179 genes up-regulated and 74 genes down-regulated by mRNA high-throughput sequencing, and the enriched functions and pathways of differential genes were mainly related to immunity response. In vivo experiments revealed that overexpression of SLAP2 inhibited the growth of tumor in nude mice, decreased the expression of ki67 in tumor tissues, and increased the rate of apoptosis in tumor tissues. Meanwhile, we found that overexpression of SLAP2 promoted macrophage polarization toward M1 type and inhibited M2 type polarization in tumors. In vitro experiments further verified its effect on M1/M2 polarization by transfecting SLAP2 overexpressing lentivirus. By transwell co-culture system, we further demonstrated that overexpression of SLAP2 inhibits cell proliferation and invasion, promotes apoptosis, up-regulates the expression of Bax in cells, and down-regulates the expression of Bcl-2 in cells by promoting macrophage M1-type polarization. Overexpression of SLAP2 inhibits TNBC progression by promoting macrophage M1-type polarization.
    Keywords:  Apoptosis; Macrophage; Proliferation; SLAP2; Triple-negative breast cancer
    DOI:  https://doi.org/10.1038/s41598-024-75922-z
  6. Front Oncol. 2024 ;14 1476459
    Gluconeogenesis and glycogenolysis required in metastatic breast cancer cells.
    Emily Hicks, Marjorie Anne Layosa, Chaylen Andolino, Caitlin Truffer, Yazhen Song, Timothy D Heden, Shawn S Donkin, Dorothy Teegarden.
       Introduction: Metabolic adaptability, including glucose metabolism, enables cells to survive multiple stressful environments. Glycogen may serve as a critical storage depot to provide a source of glucose during times of metabolic demand during the metastatic cascade; therefore, understanding glycogen metabolism is critical. Our goal was to determine mechanisms driving glycogen accumulation and its role in metastatic (MCF10CA1a) compared to nonmetastatic (MCF10A-ras) human breast cancer cells.
    Methodology: 13C6-glucose flux analysis in combination with inhibitors of the gluconeogenic pathway via phosphoenolpyruvate carboxykinase (PCK), the anaplerotic enzyme pyruvate carboxylase (PC), and the rate-limiting enzyme of the pentose phosphate pathway (PPP) glucose 6-phosphate dehydrogenase (G6PD). To determine the requirement of glycogenolysis for migration or survival in extracellular matrix (ECM) detached conditions, siRNA inhibition of glycogenolysis (liver glycogen phosphorylase, PYGL) or glycophagy (lysosomal enzyme α-acid glucosidase, GAA) enzymes was utilized.
    Results: Metastatic MCF10CA1a cells had 20-fold greater glycogen levels compared to non-metastatic MCF10A-ras cells. Most glucose incorporated into glycogen of the MCF10CA1a cells was in the five 13C-containing glucose (M+5) instead of the expected M+6 glycogen-derived glucose moiety, which occurs through direct glucose conversion to glycogen. Furthermore, 13C6-glucose in glycogen was quickly reduced (~50%) following removal of 13C-glucose. Incorporation of 13C6-glucose into the M+5 glucose in the glycogen stores was reduced by inhibition of PCK, with additional contributions from flux through the PPP. Further, inhibition of PC reduced total glycogen content. However, PCK inhibition increased total unlabeled glucose accumulation into glycogen, suggesting an alternative pathway to glycogen accumulation. Inhibition of the rate-limiting steps in glycogenolysis (PYGL) or glycophagy (GAA) demonstrated that both enzymes are necessary to support MCF10CA1a, but not MCF10A-ras, cell migration. GAA inhibition, but not PYGL, reduced viability of MCF10CA1a cells, but not MCF10A-ras, in ECM detached conditions.
    Conclusion: Our results indicate that increased glycogen accumulation is primarily mediated through the gluconeogenesis pathway and that glycogen utilization is required for both migration and ECM detached survival of metastatic MCF10CA1a cells. These results suggest that glycogen metabolism may play an important role in the progression of breast cancer metastasis.
    Keywords:  breast cancer; gluconeogenesis; glucose; glycogen; glycogenolysis; glycophagy
    DOI:  https://doi.org/10.3389/fonc.2024.1476459
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