bims-merabr 2024-07-28 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2024–07–28
nine papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

FANCI Inhibition Induces PARP1 Redistribution to Enhance the Efficacy of PARP Inhibitors in Breast Cancer.
Progesterone Receptor Signaling Promotes Cancer Associated Fibroblast Mediated Tumorigenicity in ER+ Breast Cancer.
Targeting POLD1 to suppress the proliferation and migration of breast cancer MDA-MB-231 cell lines by downregulation of SIRT1.
Downregulation of tRF-Cys-GCA-029 by hyperglycemia promotes tumorigenesis and glycolysis of diabetic breast cancer through upregulating PRKCG translation.
Inverse FASN and LDHA correlation drives metabolic resistance in breast cancer.
PTX promotes breast cancer migration and invasion by recruiting ATF4 to upregulate FGF19.
Polyamine Anabolism Promotes Chemotherapy-Induced Breast Cancer Stem Cell Enrichment.
GluOC promotes proliferation and metastasis of TNBC through the ROCK1 signaling pathway.
Comparative Analysis of Breast Cancer Metabolomes Highlights Fascin's Central Role in Regulating Key Pathways Related to Disease Progression.

Cancer Res. 2024 Jul 22.

FANCI Inhibition Induces PARP1 Redistribution to Enhance the Efficacy of PARP Inhibitors in Breast Cancer.

Yu-Zhou Huang, Ming-Yi Sang, Pei-Wen Xi, Ruo-Xi Xu, Meng-Yuan Cai, Zi-Wen Wang, Jianyi Zhao, Yi-Han Li, Ji-Fu Wei, Qiang Ding.

Breast cancer is a global public health concern with high mortality rates, necessitating the development of innovative treatment strategies. PARP inhibitors have shown efficacy in certain patient populations, but their application is largely limited to cancers with homologous recombination deficiency. Here, we identified the suppression of FANCI as a therapeutic strategy to enhance the efficacy of PARP inhibitors in breast cancer. Elevated FANCI expression in breast cancer was associated with poor prognosis and increased cell proliferation and migration. FANCI interacted with PARP1, and suppressing FANCI limited the nuclear localization and functionality of PARP1. Importantly, FANCI inhibition sensitized breast cancer cells to the PARP inhibitor talazoparib in the absence of BRCA mutations. Additionally, the CDK4/6 inhibitor palbociclib enhanced the sensitivity of breast cancer cells to talazoparib through FANCI inhibition. These findings highlight the potential of targeting FANCI to enhance the efficacy of PARP inhibitors in treating breast cancer.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-2738
Endocrinology. 2024 Jul 23. pii: bqae092. [Epub ahead of print]

Progesterone Receptor Signaling Promotes Cancer Associated Fibroblast Mediated Tumorigenicity in ER+ Breast Cancer.

Caroline H Diep, Angela Spartz, Thu H Truong, Amy R Dwyer, Dorraya El-Ashry, Carol A Lange.

  Breast cancer progression involves intricate interactions between cancer cells and the tumor microenvironment (TME). This study elucidates the critical role of progesterone receptor (PR) signaling in mediating the pro-tumorigenic effects of cancer-associated fibroblasts (CAFs) on estrogen receptor-positive (ER+) luminal breast cancer cells. We demonstrate that CAFs produce physiologically relevant levels of estrogen and progesterone, which significantly contribute to breast cancer tumorigenicity. Specifically, CAF-conditioned media promoted PR-dependent anchorage-independent growth, tumorsphere formation/stem cell expansion, and CD44 upregulation. CAF cells formed co-clusters more frequently with PR+ breast cancer cells relative to PR-null models. While both PR isoforms mediated these actions, PR-A was a dominant driver of tumorsphere formation/stemness, while PR-B induced robust CD44 expression and CAF/tumor cell co-cluster formation. CD44 knockdown impaired CAF/tumor cell co-clustering. Fibroblast growth factor 2 (FGF2), also secreted by CAFs, phosphorylated PR (Ser294) in a MAPK-dependent manner and activated PR to enhance CD44 expression and breast cancer tumorigenicity. The FGFR inhibitor, PD173074, diminished CAF- and FGF2-dependent PR activation, tumorsphere formation, and co-clustering. In summary, this study reveals a novel mechanism through which stromal CAFs orchestrate elevated PR signaling in ER+ luminal breast cancer via secretion of both progesterone and FGF2, a potent activator of ERK1/2. Understanding tumor cell/TME interactions provides insights into potential therapeutic strategies aimed at disrupting PR- and/or FGF2/FGFR-dependent signaling pathways to prevent early metastasis in ER+ breast cancer patients.

Keywords:  CAF; FGF2; PD173074; breast cancer; progesterone

DOI:  https://doi.org/10.1210/endocr/bqae092
Toxicol Res (Camb). 2024 Aug;13(4): tfae111

Targeting POLD1 to suppress the proliferation and migration of breast cancer MDA-MB-231 cell lines by downregulation of SIRT1.

Areege Ibrahim Salih, Basma Talib Al-Sudani, Bahir Abdul-Razzaq Mshimesh.

   Background: The resistant and aggressive nature of triple-negative breast cancer (TNBC) renders it mostly incurable even following extensive multimodal treatment. Therefore, more studies are required to understand the underlying molecular mechanisms of its pathogenesis. SIRT1 is a class III histone deacetylase NAD + -dependent enzyme that is interlinked in tumor progression, apoptosis, metastasis, and other mechanisms of tumorigenesis, while DNA polymerase delta 1 (POLD1) functions as a gene coding for p125, which plays an important role in genome stability and DNA replication.
Objective: We aimed to investigate the downstream signaling pathway of EX-527, a potent and selective SIRT1 inhibitor, in MDA-MB-231 breast cancer cell lines, and the crosstalk between SIRT1 and POLD1, which is essential for the activities of polymerase δ.
Methods: The antiproliferative and apoptotic effects of EX-527 on MDA-MB-231 cells were assessed by MTT and annexin V/PI double staining assays. Migration and invasion activity of MDA-MB-231 cells were assessed by wound-healing scratch and transwell assays. Protein expressions were examined using Western Blot analysis.
Results: MDA-MB-231 cells treatment with IC50 values of 45.3 μM EX-527 significantly suppressed cell proliferation and induced apoptosis by down-regulating SIRT1. Also, it significantly repressed migration and invasion of MDA-MB-231 cells as evaluated by wound healing and transwell invasion assays. Western blot results showed that decreased expression of SIRT1 is positively correlated with expression of p53 along with down-regulating POLD1.
Conclusion: SIRT1 could have an oncogenic role in breast cancer development and progression via activating POLD1. These conclusions present new insights into the underlying mechanisms of TNBC.

Keywords:  Breast cancer; EX-527; MDA-MB-231; POLD1; SIRT1 inhibitor

DOI:  https://doi.org/10.1093/toxres/tfae111
Breast Cancer Res. 2024 Jul 22. 26(1): 117

Downregulation of tRF-Cys-GCA-029 by hyperglycemia promotes tumorigenesis and glycolysis of diabetic breast cancer through upregulating PRKCG translation.

Yongyi Huang, Cheng Chen, Yang Liu, Binbin Tan, Qin Xiang, Qianqian Chen, Yiling Wang, Wenhan Yang, Jingsong He, Duanyang Zhou, Yuting Wang, Kaiping Gao, Duo Zheng, Rihong Zhai.

   BACKGROUND: Diabetes mellitus (DM) affects up to one-third of breast cancer (BC) patients. Patients with co-existing BC and DM (BC-DM) have worsened BC prognosis. Nevertheless, the molecular mechanisms orchestrating BC-DM prognosis remain poorly understood. tRNA-derived fragments (tRFs) have been shown to regulate cancer progression. However, the biological role of tRFs in BC-DM has not been explored.
METHODS: tRF levels in tumor tissues and cells were detected by tRF sequencing and qRT-PCR. The effects of tRF on BC cell malignancy were assessed under euglycemic and hyperglycemic conditions in vitro. Metabolic changes were assessed by lactate, pyruvate, and extracellular acidification rate (ECAR) assays. Diabetic animal model was used to evaluate the impacts of tRF on BC tumor growth. RNA-sequencing (RNA-seq), qRT-PCR, Western blot, polysome profiling, luciferase reporter assay, and rescue experiments were performed to explore the regulatory mechanisms of tRF in BC-DM.
RESULTS: We identified that tRF-Cys-GCA-029 was downregulated in BC-DM tissues and under hyperglycemia conditions in BC cells. Functionally, downregulation of tRF-Cys-GCA-029 promoted BC cell proliferation and migration in a glucose level-dependent manner. tRF-Cys-GCA-029 knockdown also enhanced glycolysis metabolism in BC cells, indicated by increasing lactate/pyruvate production and ECAR levels. Notably, injection of tRF-Cys-GCA-029 mimic significantly suppressed BC tumor growth in diabetic-mice. Mechanistically, tRF-Cys-GCA-029 regulated BC cell malignancy and glycolysis via interacting with PRKCG in two ways: binding to the coding sequence (CDS) of PRKCG mRNA to regulate its transcription and altering polysomal PRKCG mRNA expression to modify its translation.
CONCLUSIONS: Hyperglycemia-downregulated tRF-Cys-GCA-029 enhances the malignancy and glycolysis of BC cells. tRF-Cys-GCA-029-PRKCG-glycolysis axis may be a potential therapeutic target against BC-DM.

Keywords:  Diabetic breast cancer; Glycolysis; Hyperglycaemia; PRKCG; tRF-Cys-GCA-029

DOI:  https://doi.org/10.1186/s13058-024-01870-1
J Transl Med. 2024 Jul 24. 22(1): 676

Inverse FASN and LDHA correlation drives metabolic resistance in breast cancer.

Chiara Papulino, Ugo Chianese, Ahmad Ali, Gregorio Favale, Concetta Tuccillo, Fortunato Ciardiello, Annabella Di Mauro, Chiara Mignogna, Gerardo Ferrara, Alfredo Budillon, Wouter Leonard Megchelenbrink, Nunzio Del Gaudio, Mariarosaria Conte, Fabrizio Merciai, Pietro Campiglia, Lucia Altucci, Vincenzo Carafa, Eduardo Sommella, Rosaria Benedetti.

   BACKGROUND: Breast cancer manifests as a heterogeneous pathology marked by complex metabolic reprogramming essential to satisfy its energy demands. Oncogenic signals boost the metabolism, modifying fatty acid synthesis and glucose use from the onset to progression and therapy resistant-forms. However, the exact contribution of metabolic dependencies during tumor evolution remains unclear.
METHODS: In this study, we elucidate the connection between FASN and LDHA, pivotal metabolic genes, and their correlation with tumor grade and therapy response using datasets from public repositories. Subsequently, we evaluated the metabolic and proliferative functions upon FASN and LDHA inhibition in breast cancer models. Lastly, we integrated metabolomic and lipidomic analysis to define the contributions of metabolites, lipids, and precursors to the metabolic phenotypes.
RESULTS: Collectively, our findings indicate metabolic shifts during breast cancer progression, unvealling two distinct functional energy phenotypes associated with aggressiveness and therapy response. Specifically, FASN exhibits reduced expression in advance-grade tumors and therapy-resistant forms, whereas LDHA demonstrates higher expression. Additionally, the biological and metabolic impact of blocking the enzymatic activity of FASN and LDHA was correlated with resistant conditions.
CONCLUSIONS: These observations emphasize the intrinsic metabolic heterogeneity within breast cancer, thereby highlighting the relevance of metabolic interventions in the field of precision medicine.

Keywords:  Breast cancer; FASN; LDHA; Metabolism; Tamoxifen resistance

DOI:  https://doi.org/10.1186/s12967-024-05517-9
Cell Signal. 2024 Jul 23. pii: S0898-6568(24)00277-8. [Epub ahead of print] 111309

PTX promotes breast cancer migration and invasion by recruiting ATF4 to upregulate FGF19.

Ting Xue, Xuezhen Wang, Xianjun Pan, Mei Liu, Faliang Xu.

   BACKGROUND: Widely-spread among women, breast cancer is a malignancy with fatalities, and chemotherapy is a vital treatment option for it. Recent studies have underscored the potential of chemotherapeutic agents such as paclitaxel, adriamycin, cyclophosphamide, and gemcitabine, among others, in facilitating tumor metastasis, with paclitaxel being extensively researched in this context. The molecular mechanism of these genes and their potential relevance to breast cancer is noteworthy.
METHOD: Clinical tissue specimens were used to analyze the expression and clinical significance of FGF19 or P-FGFR4 in patients with breast cancer before and after chemotherapy. qRT-PCR, ELISA, immunofluorescence and Western blotting were used to detect the expression level of FGF19 in breast cancer cells. The biological impacts of paclitaxel, FGF19, and ATF4 on breast cancer cells were assessed through CCK8, Transwell, and Western blot assays. The expression of ATF4 in breast cancer cells was determined through database analysis, Western blot analysis, qRT-PCR, and immunofluorescence. The direct interaction between FGF19 and ATF4 was confirmed by a luciferase assay, and Western blotting was used to assess the levels of key proteins in the stress response pathway. To confirm the effects of PTX and FGF19 in vivo, we established a lung metastasis model in nude mice.
RESULTS: FGF19 expression was increased in breast cancer patients after chemotherapy. Paclitaxel can boost the migration and invasion of breast cancer cells, accompanied by an increase in FGF19 expression. ATF4 might be involved in facilitating the enhancing effect of FGF19 on breast cancer cell migration. Finally, stimulation during paclitaxel treatment could trigger a stress response, influencing the expression of FGF19 and the migration of breast cancer cells.
CONCLUSION: These data suggest that paclitaxel regulates FGF19 expression through ATF4 and thus promotes breast cancer cell migration and invasion.

Keywords:  ATF4; Breast cancer; FGF19; Metastasis; Paclitaxel

DOI:  https://doi.org/10.1016/j.cellsig.2024.111309
Adv Sci (Weinh). 2024 Jul 26. e2404853

Polyamine Anabolism Promotes Chemotherapy-Induced Breast Cancer Stem Cell Enrichment.

Guangyu Ji, Jia Liu, Zhiqun Zhao, Jie Lan, You Yang, Zheng Wang, Huijing Feng, Kai Ji, Xiaofeng Jiang, Huize Xia, Guangyao Wei, Yajing Zhang, Yuhong Zhang, Xinlong Du, Yawen Wang, Yuanyuan Yang, Zhaojian Liu, Kai Zhang, Qi Mei, Rong Sun, Haiquan Lu.

  Breast cancer patients may initially benefit from cytotoxic chemotherapy but experience treatment resistance and relapse. Chemoresistant breast cancer stem cells (BCSCs) play a pivotal role in cancer recurrence and metastasis, however, identification and eradication of BCSC population in patients are challenging. Here, an mRNA-based BCSC signature is developed using machine learning strategy to evaluate cancer stemness in primary breast cancer patient samples. Using the BCSC signature, a critical role of polyamine anabolism in the regulation of chemotherapy-induced BCSC enrichment, is elucidated. Mechanistically, two key polyamine anabolic enzymes, ODC1 and SRM, are directly activated by transcription factor HIF-1 in response to chemotherapy. Genetic inhibition of HIF-1-controlled polyamine anabolism blocks chemotherapy-induced BCSC enrichment in vitro and in xenograft mice. A novel specific HIF-1 inhibitor britannin is identified through a natural compound library screening, and demonstrate that coadministration of britannin efficiently inhibits chemotherapy-induced HIF-1 transcriptional activity, ODC1 and SRM expression, polyamine levels, and BCSC enrichment in vitro and in xenograft and autochthonous mouse models. The findings demonstrate the key role of polyamine anabolism in BCSC regulation and provide a new strategy for breast cancer treatment.

Keywords:  HIF‐1 inhibitor; breast cancer stem cell; britannin; chemotherapy; hypoxia‐inducible factor 1; polyamine anabolism

DOI:  https://doi.org/10.1002/advs.202404853
Cancer Cell Int. 2024 Jul 25. 24(1): 263

GluOC promotes proliferation and metastasis of TNBC through the ROCK1 signaling pathway.

Jiaojiao Xu, Keting Dong, Xue Bai, Miao Zhang, Qian Du, Lei Chen, Jianhong Yang.

   BACKGROUND: Triple negative breast cancer (TNBC) is a type of breast cancer that is negative for oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2, is highly malignant and aggressive, lacks of corresponding targeted therapy, and has a relatively poor prognosis. Therefore, understanding the mechanism of TNBC development and formulating effective treatment strategies for inducing cell death are still urgent tasks in the treatment of TNBC. Research has shown that uncarboxylated osteocalcin can promote the proliferation of prostate cancer, lung adenocarcinoma and TNBC cells, but the mechanism by which GluOC affects TNBC growth and metastasis needs further study.
METHODS: MDA-MB-231 breast cancer cells were used for in vitro cell analysis. Key target molecules or pathways were identified by RNA sequencing, and migration ability was detected by scratch assays, Transwell assays, cell adhesion assays and western blot analysis. Fluorescence staining, colony detection, qRT‒PCR and flow cytometry were used to detect apoptosis, oxidative stress, the cell cycle and the stemness of cancer cells, and a xenotransplantation model in BALB/C nude mice was used for in vivo analysis.
RESULTS: This study demonstrated that GluOC facilitates the migration of MDA-MB-231 breast cancer cells through the ROCK1/MYPT1/MLC2 signalling pathway and promotes the proliferation of TNBC cells via the ROCK1/JAK2/PIK3CA/AKT signalling pathway. Experiments in nude mice demonstrated that GluOC promoted tumour cell proliferation and metastasis in tumour-bearing mice, which further clarified the molecular mechanism of TNBC growth and invasion.
CONCLUSION: Our findings highlight the importance of GluOC in driving TNBC progression and its association with poor patient outcomes. This study clarifies the functional effects of GluOC on TNBC growth, providing insight into the molecular basis of TNBC and potentially providing new ideas for developing targeted therapies to improve patient outcomes.

Keywords:  Metastasis; Osteocalcin; Proliferation; ROCK1; TNBC

DOI:  https://doi.org/10.1186/s12935-024-03445-8
Int J Mol Sci. 2024 Jul 18. pii: 7891. [Epub ahead of print]25(14):

Comparative Analysis of Breast Cancer Metabolomes Highlights Fascin's Central Role in Regulating Key Pathways Related to Disease Progression.

Reem H AlMalki, Huda K Al-Nasrallah, Alanoud Aldossry, Rayanah Barnawi, Samiyah Al-Khaldi, Sheema Almozyan, Mysoon M Al-Ansari, Hazem Ghebeh, Anas M Abdel Rahman, Monther Al-Alwan.

  Omics technologies provide useful tools for the identification of novel biomarkers in many diseases, including breast cancer, which is the most diagnosed cancer in women worldwide. We and others have reported a central role for the actin-bundling protein (fascin) in regulating breast cancer disease progression at different levels. However, whether fascin expression promotes metabolic molecules that could predict disease progression has not been fully elucidated. Here, fascin expression was manipulated via knockdown (fascinKD+NORF) and rescue (fascinKD+FORF) in the naturally fascin-positive (fascinpos+NORF) MDA-MB-231 breast cancer cells. Whether fascin dysregulates metabolic profiles that are associated with disease progression was assessed using untargeted metabolomics analyses via liquid chromatography-mass spectrometry. Overall, 12,226 metabolic features were detected in the tested cell pellets. Fascinpos+NORF cell pellets showed 2510 and 3804 significantly dysregulated metabolites compared to their fascinKD+NORF counterparts. Fascin rescue (fascinKD+FORF) revealed 2710 significantly dysregulated cellular metabolites compared to fascinKD+NORF counterparts. A total of 101 overlapped cellular metabolites between fascinKD+FORF and fascinpos+NORF were significantly dysregulated in the fascinKD+NORF cells. Analysis of the significantly dysregulated metabolites by fascin expression revealed their involvement in the metabolism of sphingolipid, phenylalanine, tyrosine, and tryptophan biosynthesis, and pantothenate and CoA biosynthesis, which are critical pathways for breast cancer progression. Our findings of fascin-mediated alteration of metabolic pathways could be used as putative poor prognostic biomarkers and highlight other underlying mechanisms of fascin contribution to breast cancer progression.

Keywords:  breast cancer; fascin; metabolic pathways; untargeted metabolomics

DOI:  https://doi.org/10.3390/ijms25147891