bims-merabr 2024-09-15 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2024‒09‒15
eight papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

Downregulation of CIAPIN1 regulates the proliferation, migration and glycolysis of breast cancer cells via inhibition of STAT3 pathway.
SNHG14 promotes triple-negative breast cancer cell proliferation, invasion, and chemoresistance by regulating the ERK/MAPK signaling pathway.
LSD1 inhibits the invasion and migration of breast cancer through exosomes.
BMP4-Induced Suppression of Breast Cancer Metastasis Is Associated with Inhibition of Cholesterol Biosynthesis.
Blocking of SIRT7/FOXO3a Axis by miR-152-3p Enhances Cisplatin Sensitivity in Breast Cancer.
ALDH1A3 is the switch that determines the balance of ALDH+ and CD24-CD44+ cancer stem cells, EMT-MET, and glucose metabolism in breast cancer.
ASCT2 Regulates Fatty Acid Metabolism to Trigger Glutamine Addiction in Basal-like Breast Cancer.
Breast Cancer Stem Cells Upregulate IRF6 in Stromal Fibroblasts to Induce Stromagenesis.

Sci Rep. 2024 09 05. 14(1): 20794

Downregulation of CIAPIN1 regulates the proliferation, migration and glycolysis of breast cancer cells via inhibition of STAT3 pathway.

Hao Yuan, Ming Zhong, Jie Liu, Shuya Tang, Hongbo Zhu, Qingping Wei, Bingbing Pu, Yongping Li.

  Cytokine-induced apoptosis inhibitor 1 (CIAPIN1) is a protein that regulates apoptosis and programmed cell death. This research aims to evaluate its potential role in inhibiting breast cancer cell proliferation, migration, and glycolysis and uncover its underlying molecular mechanism. We collected breast cancer tissue samples from eight patients between January 2019 and June 2023 in our Hospital to analyse CIAPIN1 expression. We transfected human breast cancer cell lines (MCF7, MDA-MB-231, MDA-MB-453, and MDA-MB-468) with siRNA of CIAPIN1. Finally, we determined protein expression using RT-qPCR and Western blotting. CIAPIN1 expression was elevated in both breast cancer tissue and serum. Overexpression of CIAPIN1 detected in the breast cancer cell lines MCF7 and MDA-MB-468. In addition, CIAPIN1 overexpression increased cell proliferation and migration rate. CIAPIN1 downregulation suppressed cell proliferation while elevated cellular apoptosis, reactive oxygen species (ROS) production and oxidative stress in breast cancer cells. Moreover, CIAPIN1 inhibition remarkably suppressed pyruvate, lactate and adenosine triphosphate (ATP) production and reduced the pyruvate kinase M2 (PKM2) protein expression and phosphorylation of signal transducer and activator of transcription 3 (STAT3) in breast cancer cells. Downregulation of CIAPIN1 suppresses cell proliferation, migration and glycolysis capacity in breast cancer cells by inhibiting the STAT3/PKM2 pathway.

Keywords:  Apoptosis; Breast cancer; Cytokine-induced apoptosis inhibitor 1; Reactive oxygen species; Signal transducer and activator of transcription 3

DOI:  https://doi.org/10.1038/s41598-024-71405-3
IUBMB Life. 2024 Sep 12.

SNHG14 promotes triple-negative breast cancer cell proliferation, invasion, and chemoresistance by regulating the ERK/MAPK signaling pathway.

Bin Wang, Ai-Yan Xing, Guang-Xin Li, Long Liu, Chungen Xing.

  The functional role and molecular mechanisms of small-nucleolar RNA host gene 14 (SNHG14) in triple-negative breast cancer (TNBC) progression remain unclear. The expression levels of SNHG14 in breast cancer samples and cell lines were determined using real-time quantitative polymerase chain reaction. Cell proliferation, migration, and invasion abilities were detected using MTS and transwell assays. By RNA sequencing, differentially expressed genes were identified between the SNHG14 siRNA and the negative control group. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were used to predict the targets and pathways regulated by SNHG14. pRAF, pMEK, and pERK expression were measured by western blot. The xenograft model was constructed to access the biological function of SNHG14 in vivo. A minimal patient-derived xenograft model was established to evaluate the sensitivity to chemotherapy drugs. Our data indicated that SNHG14 expression was increased in TNBC tissues and cell lines. SNHG14 knockdown attenuated the proliferation, migration, and invasion abilities of TNBC cells both in vivo and in vitro. High SNHG14 expression was associated with lymph node metastasis and a high Ki67 index. The targets of SNHG14 were mainly enriched in the MAPK signaling pathway. pRAF, pMEK, and pERK expression were downregulated after being transfected with SNHG14 siRNA. Compared with the negative control group, the expression of CACNA1I, DUSP8, FGF17, FGFR4, FOS, PDGFRB, and DDIT3 was increased, and the expression of MKNK1 was decreased in the SNHG14 siRNA group. Minimal patient-derived xenograft model demonstrated that knockdown of SNHG14 enhanced the sensitivity to Docetaxel in vivo. Compared with the DMSO group, the proliferation of Docetaxel-resistant MDA-MB-231 cells was decreased in Dabrafenib, PD184352, and FR180204 treatment groups. SNHG14 knockdown inhibits TNBC progression by regulating the ERK/MAPK signaling pathway, which provides evidence for SNHG14 as a potential target for TNBC therapy.

Keywords:  MAPK pathway; SNHG14; TNBC; invasion; proliferation

DOI:  https://doi.org/10.1002/iub.2910
Sci Rep. 2024 09 06. 14(1): 20817

LSD1 inhibits the invasion and migration of breast cancer through exosomes.

Nan Zhang, Zhongyu Chen, Benkai Xin, Yueru Shi, Yutong Yao, Jingtong Yang, Xiaoyu Wang, Xin Hu.

  Metastasis accounts for almost 90% of breast cancer-related fatalities, making it frequent malignancy and the main reason of tumor mortality globally among women. LSD1 is a histone demethylase, which plays an important role in breast cancer. In order to explore the effect of LSD1 on invasion and migration of breast cancer, we treated breast cancer cells with MCF7 and T47D exosomes knocked down by LSD1, and the invasion and migration of breast cancer cells were significantly enhanced. This phenomenon indicates that LSD1 can inhibit the invasion and migration of breast cancer cells. miR-1290 expression was downregulated in LSD1 knockdown MCF7 exosomes. By analyzing the database of miR-1290 target gene NAT1, we verified that miR-1290 could regulate the expression of NAT1. These data provide fresh insights into the biology of breast cancer therapy by demonstrating how the epigenetic factor LSD1 stimulates the breast cancer cells' invasion and migration via controlling exosomal miRNA.

Keywords:  Exosome; LSD1; miR-1290

DOI:  https://doi.org/10.1038/s41598-024-71353-y
Int J Mol Sci. 2024 Aug 23. pii: 9160. [Epub ahead of print]25(17):

BMP4-Induced Suppression of Breast Cancer Metastasis Is Associated with Inhibition of Cholesterol Biosynthesis.

Lap Hing Chi, Andrew D Redfern, Terry C C Lim Kam Sian, Ian P Street, Allan D Burrows, Suraya Roslan, Roger J Daly, Robin L Anderson.

  We reported previously that in preclinical models, BMP4 is a potent inhibitor of breast cancer metastasis and that high BMP4 protein levels predict favourable patient outcomes. Here, we analysed a breast cancer xenograft with or without enforced expression of BMP4 to gain insight into the mechanisms by which BMP4 suppresses metastasis. Transcriptomic analysis of cancer cells recovered from primary tumours and phosphoproteomic analyses of cancer cells exposed to recombinant BMP4 revealed that BMP4 inhibits cholesterol biosynthesis, with many genes in this biosynthetic pathway being downregulated by BMP4. The treatment of mice bearing low-BMP4 xenografts with a cholesterol-lowering statin partially mimicked the anti-metastatic activity of BMP4. Analysis of a cohort of primary breast cancers revealed a reduced relapse rate for patients on statin therapy if their tumours exhibited low BMP4 levels. These findings indicate that BMP4 may represent a predictive biomarker for the benefit of additional statin therapy in breast cancer patients.

Keywords:  BMP4; breast cancer; cholesterol biosynthesis; metastasis; statins

DOI:  https://doi.org/10.3390/ijms25179160
Am J Med Sci. 2024 Sep 04. pii: S0002-9629(24)01444-7. [Epub ahead of print]

Blocking of SIRT7/FOXO3a Axis by miR-152-3p Enhances Cisplatin Sensitivity in Breast Cancer.

Xiangkui Shi, Yunfei Ji, Xueqing Wu, Yu Du, Xiaonan Yan, Yan Wang, Xiaobing Xia.

  BACKGROUND: Cisplatin-based chemoresistance is major obstacle for breast cancer (BC) including Triple-negative breast cancer (TNBC). SIRT7 is reportedly involved in the progression of BC, the underlining mechanism in Cisplatin-based chemoresistance in BC remains unclear. This work is to elucidate effects of SIRT7 on cisplatin resistance in breast cancer regulated by miR-152-3p.METHODS: The RNA expression of SIRT7 and miRNAs in breast cancer were available from TCGA database. SIRT7-targeted miRNAs were predicted by TargetScan, miRanda, miRDB databases. The association of SIRT7 expression with predicted miRNA was validated by Luciferase assay. Cell apoptosis was determined by Flow cytometry. Cell viability was detected by CCK8 assay. The mRNA expression was measured by quantitative real-time polymerase chain reaction (qRT-PCR) assay. Protein expression was determined by Western blotting assay.
RESULTS: SIRT7 mRNA levels were dramatically enhanced in BC tissues compared to para-carcinoma tissues, also increased in BC patients with Cisplatin-based chemotherapy containing TNBC compared with those without. The increase of SIRT7 expression was obviously relevant to shorter survive time of them. Importantly, SIRT7 inhibition facilitated Cisplatin-induced cell apoptosis of TNBC (MDA-MB-231 and MDA-MB-468) and non- TNBC (MCF-7). Notably, miR-152-3p was predicted as a negative regulator of SIRT7 by overlapping downregulated miRNAs in BC patients treated with Cisplatin-based chemotherapy and miRNAs to target SIRT7. Mechanically, miR-152-3p blocked SIRT7 to stimulate an activation of FOXO3a, cleaved PARP1 and Caspase-3, sensitizing Cisplatin-induced apoptosis of BC cells.
CONCLUSIONS: Inhibition of SIRT7 by miR-152-3p may be a promising strategy against the resistance to cisplatin-based chemotherapy in BC containing TNBC.

Keywords:  Breast cancer; SIRT7; cisplatin; miR-152; resistance

DOI:  https://doi.org/10.1016/j.amjms.2024.08.028
Oncogene. 2024 Sep 09.

ALDH1A3 is the switch that determines the balance of ALDH+ and CD24-CD44+ cancer stem cells, EMT-MET, and glucose metabolism in breast cancer.

Wasundara Fernando, Brianne M Cruickshank, Raj Pranap Arun, Maya R MacLean, Hannah F Cahill, Fiorella Morales-Quintanilla, Cheryl A Dean, Marie-Claire D Wasson, Margaret L Dahn, Krysta M Coyle, Olivia L Walker, Melanie R Power Coombs, Paola Marcato.

Plasticity is an inherent feature of cancer stem cells (CSCs) and regulates the balance of key processes required at different stages of breast cancer progression, including epithelial-to-mesenchymal transition (EMT) versus mesenchymal-to-epithelial transition (MET), and glycolysis versus oxidative phosphorylation. Understanding the key factors that regulate the switch between these processes could lead to novel therapeutic strategies that limit tumor progression. We found that aldehyde dehydrogenase 1A3 (ALDH1A3) regulates these cancer-promoting processes and the abundance of the two distinct breast CSC populations defined by high ALDH activity and CD24-CD44+ cell surface expression. While ALDH1A3 increases ALDH+ breast cancer cells, it inversely suppresses the CD24-CD44+ population by retinoic acid signaling-mediated gene expression changes. This switch in CSC populations induced by ALDH1A3 was paired with decreased migration but increased invasion and an intermediate EMT phenotype. We also demonstrate that ALDH1A3 increases oxidative phosphorylation and decreases glycolysis and reactive oxygen species (ROS). The effects of ALDH1A3 reduction were countered with the glycolysis inhibitor 2-deoxy-D-glucose (2DG). In cell culture and tumor xenograft models, 2DG suppresses the increase in the CD24-CD44+ population and ROS induced by ALDH1A3 knockdown. Combined inhibition of ALDH1A3 and glycolysis best reduces breast tumor growth and tumor-initiating cells, suggesting that the combination of targeting ALDH1A3 and glycolysis has therapeutic potential for limiting CSCs and tumor progression. Together, these findings identify ALDH1A3 as a key regulator of processes required for breast cancer progression and depletion of ALDH1A3 makes breast cancer cells more susceptible to glycolysis inhibition.

DOI: https://doi.org/10.1038/s41388-024-03156-4
Cancers (Basel). 2024 Aug 30. pii: 3028. [Epub ahead of print]16(17):

ASCT2 Regulates Fatty Acid Metabolism to Trigger Glutamine Addiction in Basal-like Breast Cancer.

Jia Wang, Qian Zhang, Huaizi Fu, Yi Han, Xue Li, Qianlin Zou, Shengtao Yuan, Li Sun.

  As a crucial amino acid, glutamine can provide the nitrogen and carbon sources needed to support cancer cell proliferation, invasion, and metastasis. Interestingly, different types of breast cancer have different dependences on glutamine. This research shows that basal-like breast cancer depends on glutamine, while the other types of breast cancer may be more dependent on glucose. Glutamine transporter ASCT2 is highly expressed in various cancers and significantly promotes the growth of breast cancer. However, the key regulatory mechanism of ASCT2 in promoting basal-like breast cancer progression remains unclear. Our research demonstrates the significant change in fatty acid levels caused by ASCT2, which may be a key factor in glutamine sensitivity. This phenomenon results from the mutual activation between ASCT2-mediated glutamine transport and lipid metabolism via the nuclear receptor PPARα. ASCT2 cooperatively promoted PPARα expression, leading to the upregulation of lipid metabolism. Moreover, we also found that C118P could inhibit lipid metabolism by targeting ASCT2. More importantly, this research identifies a potential avenue of evidence for the prevention and early intervention of basal-like breast cancer by blocking the glutamine-lipid feedback loop.

Keywords:  ASCT2; basal-like breast cancer; glutamine; lipid metabolism

DOI:  https://doi.org/10.3390/cancers16173028
Cells. 2024 Aug 31. pii: 1466. [Epub ahead of print]13(17):

Breast Cancer Stem Cells Upregulate IRF6 in Stromal Fibroblasts to Induce Stromagenesis.

Harshini Muralidharan, Thomas Hansen, Anja Steinle, David Schumacher, Elmar Stickeler, Jochen Maurer.

  The microenvironment of a cancer stem cell (CSC) niche is often found in coexistence with cancer-associated fibroblasts (CAFs). Here, we show the first in-depth analysis of the interaction between primary triple-negative breast cancer stem cells (BCSCs) with fibroblasts. Using 2D co-culture models with specific seeding ratios, we identified stromal fibroblast aggregation at the BCSC cluster periphery, and, on closer observation, the aggregated fibroblasts was found to encircle BCSC clusters in nematic organization. In addition, collagen type I and fibronectin accumulation were also found at the BCSC-stromal periphery. MACE-Seq analysis of BCSC-encapsulating fibroblasts displayed the transformation of stromal fibroblasts to CAFs and the upregulation of fibrosis regulating genes of which the Interferon Regulatory Factor 6 (IRF6) gene was identified. Loss of function experiments with the IRF6 gene decreased fibroblast encapsulation around BCSC clusters in 2D co-cultures. In BCSC xenografts, fibroblast IRF6 expression led to an increase in the stromal area and fibroblast density in tumors, in addition to a reduction in necrotic growth. Based on our findings, we propose that fibroblast IRF6 function is an important factor in the development of the stromal microenvironment and in sustaining the BCSC tumor niche.

Keywords:  BCSC niche; BCSC–fibroblast interaction; CAF; IRF6; fibrosis; stromagenesis; triple-negative BCSC; tumor stroma

DOI:  https://doi.org/10.3390/cells13171466