bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2024–08–25
eight papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. FOXO4 suppresses cisplatin resistance of Triple-Negative Breast Cancer by inhibiting autophagy.
  2. Adipocyte-conditioned medium induces tamoxifen resistance by activating PI3K/Akt/mTOR pathway in estrogen receptor-positive breast cancer cells.
  3. The DNA repair pathway as a therapeutic target to synergize with trastuzumab deruxtecan in HER2-targeted antibody-drug conjugate-resistant HER2-overexpressing breast cancer.
  4. Restoration of TFPI2 by LSD1 inhibition suppresses tumor progression and potentiates antitumor immunity in breast cancer.
  5. The feedback loop between MTA1 and MTA3/TRIM21 modulates stemness of breast cancer in response to estrogen.
  6. Alternative splicing of ALDOA confers tamoxifen resistance in breast cancer.
  7. Gene Expression of Glycolysis Enzymes in MCF-7 Breast Cancer Cells Exposed to Warburg Effect and Hypoxia.
  8. Cancer-specific alterations in nuclear matrix proteins determined by multi-omics analyses of ductal carcinoma in situ.
  1. Am J Med Sci. 2024 Aug 16. pii: S0002-9629(24)01403-4. [Epub ahead of print]
    FOXO4 suppresses cisplatin resistance of Triple-Negative Breast Cancer by inhibiting autophagy.
    Yating Zhu, Chenguang Zhang, Qiuyu Yin, Wenting Xu, Yulou Luo, Jianghua Ou.
       BACKGROUND: Resistance to chemotherapy containing cisplatin (DDP) is a main challenge in the treatment of triple-negative breast cancer (TNBC). Forkhead box O4 (FOXO4) is frequently downregulated in DDP-resistant cells. However, it is unclear whether FOXO4 down-regulation is related to DDP resistance. Here, we investigated the relationship between FOXO4 and DDP resistance in TNBC.
    METHODS: We established the DDP-resistant cell lines MDA-MB-231/DDP and BT-549/DDP through in vitro selection. CCK-8 and colony formation assays analyzed cell growth. The resistance index was calculated. Cell autophagy was evaluated. Western blotting and qRT-PCR measured protein and gene expression. The binding between FOXO4 and TGF-β1 was determined by the dual-luciferase reporter assay.
    RESULTS: FOXO4 expression was significantly lower in MDA-MB-231/DDP and BT-549/DDP cells. FOXO4 overexpression increased the sensitivity of TNBC cells to DDP. The PI3K class Ⅲ and Beclin-1 levels and LC3-II/LC3-I ratio elevated significantly in DDP-resistant cells. Moreover, the autophagic flux was enhanced in DDP-resistant cells. 3-MA enhanced the sensitivity of TNBC cells to DDP by inhibiting autophagy. Overexpression of FOXO4, treatment with 3-MA, and their combination significantly reduced the drug resistance index. FOXO4 directly targeted TGF-β1. Additionally, TGF-β1 knockdown inhibited autophagy and restored the sensitivity of DDP-resistant cells to DDP. Mechanistically, FOXO4 affected TNBC resistance to DDP by regulating autophagy and TGF-β1.
    CONCLUSION: FOXO4 overexpression, in combination with autophagy inhibitors, can significantly improve the sensitivity of TNBC-resistant cells to DDP. These findings reveal the role and mechanism of FOXO4 in DDP sensitivity and may provide evidence for the development of TNBC therapies.
    Keywords:  FOXO4; TGF-β1; autophagy; cisplatin resistance; triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.amjms.2024.08.012
  2. Biochim Biophys Acta Mol Cell Res. 2024 Aug 17. pii: S0167-4889(24)00164-2. [Epub ahead of print]1871(7): 119821
    Adipocyte-conditioned medium induces tamoxifen resistance by activating PI3K/Akt/mTOR pathway in estrogen receptor-positive breast cancer cells.
    Masatoshi Nakatsuji, Ko Fujimori.
      Resistance to endocrine therapy is a major clinical challenge in estrogen receptor (ER)-positive breast cancer. Obesity is associated with the clinical response to ER-positive breast cancers; however, the mechanism underlying obesity-induced resistance to endocrine therapy in ER-positive breast cancers remains unclear. In this study, we investigated the molecular mechanisms underlying obesity-induced resistance to tamoxifen (TAM), an anti-estrogen agent, in the ER-positive breast cancer cell line MCF-7 using differentiated adipocyte-conditioned medium (D-CM). Treatment of the cells with D-CM promoted TAM resistance by reducing TAM-induced apoptosis. The expression levels of the ERα target genes were higher in D-CM-treated cells than those in untreated ones. In contrast, when the cells were cultured in the presence of TAM, the expression levels were decreased, with or without D-CM. Moreover, the expression of the markers for cancer stem-like cells (CSCs) and mammosphere formation was enhanced by co-treating with D-CM and TAM, compared with TAM alone. The phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway was activated in MCF-7 cells by D-CM treatment, even in the presence of TAM. Inhibition of the PI3K/Akt/mTOR pathway decreased the expression levels of the CSC markers, suppressed mammosphere formation, and resensitized to TAM via inducing apoptosis in D-CM-treated cells. These results indicate that the conditioned medium of differentiated adipocytes promoted TAM resistance by inducing the CSC phenotype through activation of the PI3K/Akt/mTOR pathway in ER-positive breast cancer cells. Thus, the PI3K/Akt/mTOR pathway may be a therapeutic target in obese patients with ER-positive breast cancers.
    Keywords:  Cancer stem-like cells; ER-positive breast cancer; Obesity; PI3K/Akt/mTOR pathway; Tamoxifen resistance
    DOI:  https://doi.org/10.1016/j.bbamcr.2024.119821
  3. J Exp Clin Cancer Res. 2024 Aug 21. 43(1): 236
    The DNA repair pathway as a therapeutic target to synergize with trastuzumab deruxtecan in HER2-targeted antibody-drug conjugate-resistant HER2-overexpressing breast cancer.
    Jangsoon Lee, Kumiko Kida, Jiwon Koh, Huey Liu, Ganiraju C Manyam, Young Jin Gi, Dileep R Rampa, Asha S Multani, Jing Wang, Gitanjali Jayachandran, Dae-Won Lee, James M Reuben, Aysegul Sahin, Lei Huo, Debu Tripathy, Seock-Ah Im, Naoto T Ueno.
       BACKGROUND: Anti-HER2 therapies, including the HER2 antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), have led to improved survival outcomes in patients with HER2-overexpressing (HER2+) metastatic breast cancer. However, intrinsic or acquired resistance to anti-HER2-based therapies remains a clinical challenge in these patients, as there is no standard of care following disease progression. The purpose of this study was to elucidate the mechanisms of resistance to T-DM1 and T-DXd in HER2+ BC patients and preclinical models and identify targets whose inhibition enhances the antitumor activity of T-DXd in HER2-directed ADC-resistant HER2+ breast cancer in vitro and in vivo.
    METHODS: Targeted DNA and whole transcriptome sequencing were performed in breast cancer patient tissue samples to investigate genetic aberrations that arose after anti-HER2 therapy. We generated T-DM1 and T-DXd-resistant HER2+ breast cancer cell lines. To elucidate their resistance mechanisms and to identify potential synergistic kinase targets for enhancing the efficacy of T-DXd, we used fluorescence in situ hybridization, droplet digital PCR, Western blotting, whole-genome sequencing, cDNA microarray, and synthetic lethal kinome RNA interference screening. In addition, cell viability, colony formation, and xenograft assays were used to determine the synergistic antitumor effect of T-DXd combinations.
    RESULTS: We found reduced HER2 expression in patients and amplified DNA repair-related genes in patients after anti-HER2 therapy. Reduced ERBB2 gene amplification in HER2-directed ADC-resistant HER2+ breast cancer cell lines was through DNA damage and epigenetic mechanisms. In HER2-directed ADC-resistant HER2+ breast cancer cell lines, our non-biased RNA interference screening identified the DNA repair pathway as a potential target within the canonical pathways to enhance the efficacy of T-DXd. We validated that the combination of T-DXd with ataxia telangiectasia and Rad3-related inhibitor, elimusertib, led to significant breast cancer cell death in vitro (P < 0.01) and in vivo (P < 0.01) compared to single agents.
    CONCLUSIONS: The DNA repair pathways contribute to HER2-directed ADC resistance. Our data justify exploring the combination treatment of T-DXd with DNA repair-targeting drugs to treat HER2-directed ADC-resistant HER2+ breast cancer in clinical trials.
    Keywords:  DNA damage repair pathway; HER2 antibody–drug conjugates; HER2+ breast cancer; HER2-directed ADC resistance; T-DXd
    DOI:  https://doi.org/10.1186/s13046-024-03143-3
  4. Cancer Lett. 2024 Aug 21. pii: S0304-3835(24)00577-9. [Epub ahead of print]600 217182
    Restoration of TFPI2 by LSD1 inhibition suppresses tumor progression and potentiates antitumor immunity in breast cancer.
    Tiezheng Gu, Shauna N Vasilatos, Jun Yin, Ye Qin, Lin Zhang, Nancy E Davidson, Yi Huang.
      Histone lysine-specific demethylase 1 (LSD1) is frequently overexpressed in triple negative breast cancer (TNBC), which is associated with worse clinical outcome in TNBC patients. However, the underlying mechanisms by which LSD1 promotes TNBC progression remain to be identified. We recently established a genetically engineered murine model by crossing mammary gland conditional LSD1 knockout mice with Brca1-deficient mice to explore the role of LSD1 in TNBC pathogenesis. Cre-mediated Brca1 loss led to higher incidence of tumor formation in mouse mammary glands, which was hindered by concurrent depletion of LSD1, indicating a critical role of LSD1 in promoting Brca1-deficient tumors. We also demonstrated that the silencing of a tumor suppressor gene, Tissue Factor Pathway Inhibitor 2 (TFPI2), is functionally associated with LSD1-mediated TNBC progression. Mouse Brca1-deficient tumors exhibited elevated LSD1 expression and decreased TFPI2 level compared to normal mammary tissues. Analysis of TCGA database revealed that TFPI2 expression is significantly lower in aggressive ER-negative or basal-like BC. Restoration of TFPI2 through LSD1 inhibition increased H3K4me2 enrichment at the TFPI2 promoter, suppressed tumor progression, and enhanced antitumor efficacy of chemotherapeutic agent. Induction of TFPI2 by LSD1 ablation downregulates activity of matrix metalloproteinases (MMPs) that in turn increases the level of cytotoxic T lymphocyte attracting chemokines in tumor environment, leading to enhanced tumor infiltration of CD8+ T cells. Moreover, induction of TFPI2 potentiates antitumor effect of LSD1 inhibitor and immune checkpoint blockade in poorly immunogenic TNBC. Together, our study identifies previously unrecognized roles of TFPI2 in LSD1-mediated TNBC progression, therapeutic response, and immunogenic effects.
    Keywords:  Chemotherapy; Immunotherapy; LSD1; TFPI2; TNBC
    DOI:  https://doi.org/10.1016/j.canlet.2024.217182
  5. Cell Death Dis. 2024 Aug 17. 15(8): 597
    The feedback loop between MTA1 and MTA3/TRIM21 modulates stemness of breast cancer in response to estrogen.
    Jingyao Zhang, Yinuo Wang, Jingjing Zhang, Xin Wang, Jiaxiang Liu, Miaomiao Huo, Ting Hu, Tianyu Ma, Die Zhang, Yu Li, Chang Guo, Yunkai Yang, Min Zhang, Baowen Yuan, Hao Qin, Xu Teng, Tianyang Gao, Xinhui Hao, Hefen Yu, Wei Huang, Binghe Xu, Yan Wang.
      The metastasis-associated protein (MTA) family plays a crucial role in the development of breast cancer, a common malignancy with a high incidence rate among women. However, the mechanism by which each member of the MTA family contributes to breast cancer progression is poorly understood. In this study, we aimed to investigate the roles of MTA1, MTA3, and tripartite motif-containing 21 (TRIM21) in the proliferation, invasion, epithelial-mesenchymal transition (EMT), and stem cell-like properties of breast cancer cells in vivo and in vitro. The molecular mechanisms of the feedback loop between MTA1 and MTA3/TRIM21 regulated by estrogen were explored using Chromatin immunoprecipitation (ChIP), luciferase reporter, immunoprecipitation (IP), and ubiquitination assays. These findings demonstrated that MTA1 acts as a driver to promote the progression of breast cancer by repressing the transcription of tumor suppressor genes, including TRIM21 and MTA3. Conversely, MTA3 inhibited MTA1 transcription and TRIM21 regulated MTA1 protein stability in breast cancer. Estrogen disrupted the balance between MTA1 and MTA3, as well as between MTA1 and TRIM21, thereby affecting stemness and the EMT processes in breast cancer. These findings suggest that MTA1 plays a vital role in stem cell fate and the hierarchical regulatory network of EMT through negative feedback loops with MTA3 or TRIM21 in response to estrogen, supporting MTA1, MTA3, and TRIM21 as potential prognostic biomarkers and MTA1 as a treatment target for future breast cancer therapies.
    DOI:  https://doi.org/10.1038/s41419-024-06942-w
  6. Oncogene. 2024 Aug 20.
    Alternative splicing of ALDOA confers tamoxifen resistance in breast cancer.
    Shiyi Yu, Rui Wu, Yue Si, Zhehao Fan, Ying Wang, Chang Yao, Rongmao Sun, Yaji Xue, Yongli Chen, Zheng Wang, Shuangshuang Dong, Ning Wang, Xinyue Ling, Zhengyan Liang, Caili Bi, Yi Yang, Weibing Dong, Haibo Sun.
      The cancer-associated alternative splicing (AS) events generate cancer-related transcripts which are involved in uncontrolled cell proliferation and drug resistance. However, the key AS variants implicated in tamoxifen (TAM) resistance in breast cancer remain elusive. In the current study, we investigated the landscape of AS events in nine pairs of primary and relapse breast tumors from patients receiving TAM-based therapy. We unrevealed a notable association between the inclusion of exon 7.2 in the 5'untranslated region (5'UTR) of ALDOA mRNA and TAM resistance. Mechanistically, the inclusion of ALDOA exon 7.2 enhances the translation efficiency of the transcript, resulting in increased ALDOA protein expression, mTOR pathway activity, and the promotion of TAM resistance in breast cancer cells. Moreover, the inclusion of exon 7.2 in ALDOA mRNA is mediated by MSI1 via direct interaction. In addition, elevated inclusion of ALDOA exon 7.2 or expression of MSI1 is associated with an unfavorable prognosis in patients undergoing endocrine therapy. Notably, treatment with Aldometanib, an ALDOA inhibitor, effectively restrains the growth of TAM-resistant breast cancer cells in vitro and in vivo. The present study unveils the pivotal role of an AS event in ALDOA, under the regulation of MSI1, in driving TAM resistance in breast cancer. Therefore, this study provides a promising therapeutic avenue targeting ALDOA to combat TAM resistance.
    DOI:  https://doi.org/10.1038/s41388-024-03134-w
  7. Int J Mol Cell Med. 2024 ;13(1): 29-45
    Gene Expression of Glycolysis Enzymes in MCF-7 Breast Cancer Cells Exposed to Warburg Effect and Hypoxia.
    Irem Bayar, Gamze Sevri Ekren Asici, Ayşegül Bildik, Funda Kiral.
      Hypoxia can cause significant changes in the glucose metabolism of cancer cells that prefer aerobic glycolysis for energy production instead of the conventional oxidative phosphorylation mechanism. In this study, breast cancer cells (MCF-7) were exposed to glucose (0-5.5-15-55 mM), during specific incubation periods (3, 6, 12, or 24 hours) under normoxic and hypoxic conditions. The expression levels of hypoxia-inducible factor-1α (HIF-1α), glucose transporter-1 (GLUT-1), and glycolytic enzymes at varying glucose concentrations in cells were investigated in the different oxygen environments. It was determined that glycolytic enzymes [Hexokinase 2 (HK2), Pyruvate Kinase M2 (PKM2), Glucose-6-phosphate dehydrogenase (G6PD), Lactate Dehydrogenase A (LDHA), Glyceraldehyde-3-phosphate Dehydrogenase (GAPDH), and Phosphofructokinase M (PFKM)] increased at the transcriptional level, especially in the first hours. This increase indicates that major metabolic reprogramming in response to hypoxia probably occurs over a short period of time. The increase in G6PD gene expression under high glucose and hypoxia conditions suggests that the pentose phosphate pathway (PPP) is used by cancer cells to synthesize necessary precursors for the cell. The results of the study showed that there is a significant interaction between hypoxia and glycolytic metabolism in cancer cells. It is thought that metabolic pathways activated by hypoxia and related genes located in these pathways will contribute to the literature by offering the potential to be target molecules for therapeutic purposes.
    Keywords:  Glucose; MCF-7; gene expression; glycolysis; hypoxia; normoxia
    DOI:  https://doi.org/10.22088/IJMCM.BUMS.13.1.29
  8. Front Oncol. 2024 ;14 1406946
    Cancer-specific alterations in nuclear matrix proteins determined by multi-omics analyses of ductal carcinoma in situ.
    Ali F Almutairy, Abdullah S Alhamed, Stephen G Grant, Miranda J Falso, Billy W Day, Colton R Simmons, Jean J Latimer.
       Introduction: Breast cancer (BC) is the most common cancer affecting women in the United States. Ductal carcinoma in situ (DCIS) is the earliest identifiable pre-invasive BC lesion. Estimates show that 14 to 50% of DCIS cases progress to invasive BC.
    Methods: Our objective was to identify nuclear matrix proteins (NMP) with specifically altered expression in DCIS and later stages of BC compared to non-diseased breast reduction mammoplasty and a contralateral breast explant culture using mass spectrometry and RNA sequencing to accurately identify aggressive DCIS.
    Results: Sixty NMPs were significantly differentially expressed between the DCIS and non-diseased breast epithelium in an isogenic contralateral pair of patient-derived extended explants. Ten of the sixty showed significant mRNA expression level differences that matched the protein expression. These 10 proteins were similarly expressed in non-diseased breast reduction cells. Three NMPs (RPL7A, RPL11, RPL31) were significantly upregulated in DCIS and all other BC stages compared to the matching contralateral breast culture and an unrelated non-diseased breast reduction culture. RNA sequencing analyses showed that these three genes were increasingly upregulated with BC progression. Finally, we identified three NMPs (AHNAK, CDC37 and DNAJB1) that were significantly downregulated in DCIS and all other BC stages compared to the isogenically matched contralateral culture and the non-diseased breast reduction culture using both proteomics and RNA sequencing techniques.
    Discussion: These genes should form the basis of, or contribute to, a molecular diagnostic panel that could identify DCIS lesions likely to be indolent and therefore not requiring aggressive treatment.
    Keywords:  biomarkers; breast cancer; breast cancer prognosis; ductal carcinoma in situ (DCIS); gene expression; proteomics
    DOI:  https://doi.org/10.3389/fonc.2024.1406946
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