bims-merabr 2024-06-23 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2024‒06‒23
eleven papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

SPDYC serves as a prognostic biomarker related to lipid metabolism and the immune microenvironment in breast cancer.
SNX14 inhibits autophagy via the PI3K/AKT/mTOR signaling cascade in breast cancer cells.
Targeting aberrant fatty acid synthesis and storage in endocrine resistant breast cancer cells.
Migratory Tumor Cells Cooperate with Cancer Associated Fibroblasts in Hormone Receptor-Positive and HER2-Negative Breast Cancer.
EP300 promotes tumor stemness via epigenetic activation of CRISP3 leading to lobaplatin resistance in triple-negative breast cancer.
KCNK1 promotes proliferation and metastasis of breast cancer cells by activating lactate dehydrogenase A (LDHA) and up-regulating H3K18 lactylation.
TROP2 regulates cisplatin sensitivity of triple-negative breast cancer cells by regulating endoplasmic reticulum stress.
Obesity Induces Temporally Regulated Alterations in the extracellular matrix that drive breast tumor invasion and metastasis.
Hypoxia-induced CTCF promotes EMT in breast cancer.
FOXK2 amplification promotes breast cancer development and chemoresistance.
Andrographolide targets EGFR to impede epithelial-mesenchymal transition in human breast cancer cells.

Immunol Res. 2024 Jun 18.

SPDYC serves as a prognostic biomarker related to lipid metabolism and the immune microenvironment in breast cancer.

Xinxin Chen, Haojie Peng, Zhentao Zhang, Changnian Yang, Yingqi Liu, Yanzhen Chen, Fei Yu, Shanshan Wu, Lixue Cao.

  Breast cancer remains the most common malignant carcinoma among women globally and is resistant to several therapeutic agents. There is a need for novel targets to improve the prognosis of patients with breast cancer. Bioinformatics analyses were conducted to explore potentially relevant prognostic genes in breast cancer using The Cancer Genome Atlas (TCGA) and The Gene Expression Omnibus (GEO) databases. Gene subtypes were categorized by machine learning algorithms. The machine learning-related breast cancer (MLBC) score was evaluated through principal component analysis (PCA) of clinical patients' pathological statuses and subtypes. Immune cell infiltration was analyzed using the xCell and CIBERSORT algorithms. Kyoto Encyclopedia of Genes and Genomes enrichment analysis elucidated regulatory pathways related to speedy/RINGO cell cycle regulator family member C (SPDYC) in breast cancer. The biological functions and lipid metabolic status of breast cancer cell lines were validated via quantitative real-time polymerase chain reaction (RT‒qPCR) assays, western blotting, CCK-8 assays, PI‒Annexin V fluorescence staining, transwell assays, wound healing assays, and Oil Red O staining. Key differentially expressed genes (DEGs) in breast cancer from the TCGA and GEO databases were screened and utilized to establish the MLBC score. Moreover, the MLBC score we established was negatively correlated with poor prognosis in breast cancer patients. Furthermore, the impacts of SPDYC on the tumor immune microenvironment and lipid metabolism in breast cancer were revealed and validated. SPDYC is closely related to activated dendritic cells and macrophages and is simultaneously correlated with the immune checkpoints CD47, cytotoxic T lymphocyte antigen-4 (CTLA-4), and poliovirus receptor (PVR). SPDYC strongly correlated with C-C motif chemokine ligand 7 (CCL7), a chemokine that influences breast cancer patient prognosis. A significant relationship was discovered between key genes involved in lipid metabolism and SPDYC, such as ELOVL fatty acid elongase 2 (ELOVL2), malic enzyme 1 (ME1), and squalene epoxidase (SQLE). Potent inhibitors targeting SPDYC in breast cancer were also discovered, including JNK inhibitor VIII, AICAR, and JW-7-52-1. Downregulation of SPDYC expression in vitro decreased proliferation, increased the apoptotic rate, decreased migration, and reduced lipid droplets. SPDYC possibly influences the tumor immune microenvironment and regulates lipid metabolism in breast cancer. Hence, this study identified SPDYC as a pivotal biomarker for developing therapeutic strategies for breast cancer.

Keywords:  Breast cancer; Chemotherapy; Lipid metabolism; Machine learning; SPDYC; Tumor immune microenvironment

DOI:  https://doi.org/10.1007/s12026-024-09505-5
J Mol Histol. 2024 Jun 13.

SNX14 inhibits autophagy via the PI3K/AKT/mTOR signaling cascade in breast cancer cells.

Sha Lv, Hongyan Jiang, Lingyan Yu, Yafei Zhang, Liangliang Sun, Junjun Xu.

  BACKGROUND: Sorting nexin 14 (SNX14) is a member of the sorting junction protein family. Its specific roles in cancer development remain unclear. Therefore, in this study, we aimed to determine the effects and underlying mechanisms of SNX14 on autophagy of breast cancer cells to aid in the therapeutic treatment of breast cancer.METHODS: In this study, we performed in vitro experiments to determine the effect of SNX14 on breast cancer cell growth. Moreover, we used an MCF7 breast cancer tumor-bearing mouse model to confirm the effect of SNX14 on tumor cell growth in vivo. We also performed western blotting and quantitative polymerase chain reaction to identify the mechanism by which SNX14 affects breast cancer MCF7 cells.
RESULTS: We found that SNX14 regulated the onset and progression of breast cancer by promoting the proliferation and inhibiting the autophagy of MCF7 breast cancer cells. In vivo experiments further confirmed that SNX14 knockdown inhibited the tumorigenicity and inhibited the growth of tumor cells in tumor tissues of nude mice. In addition, western blotting analysis revealed that SNX14 modulate the autophagy of MCF7 breast cancer cells via the phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin kinase signaling pathway.
CONCLUSION: Our findings indicate that SNX14 is an essential tumor-promoting factor in the development of breast cancer.

Keywords:   PI3K/AKT/mTOR ; SNX14 ; Apoptosis; Autophagy; Breast cancer

DOI:  https://doi.org/10.1007/s10735-024-10209-1
bioRxiv. 2024 Jun 03. pii: 2024.05.30.596684. [Epub ahead of print]

Targeting aberrant fatty acid synthesis and storage in endocrine resistant breast cancer cells.

Ashley V Ward, Duncan Riley, Jessica Finlay-Schultz, Heather M Brechbuhl, Kaitlyn B Hill, Rohan R Varshney, Peter Kabos, Michael C Rudolph, Carol A Sartorius.

Background: Lipid metabolic reprogramming is an emerging characteristic of endocrine therapy (ET) resistance in estrogen receptor-positive (ER+) breast cancer. We explored changes in lipid metabolism in ER+ breast cancer cell lines following acquired resistance to common endocrine treatments and tested efficacy of an inhibitor in current clinical trials.Methods: We derived ER+ breast cancer cell lines resistant to Tamoxifen (TamR), Fulvestrant (FulvR), and long-term estrogen withdrawal (EWD). Parental and ET resistant cells were subjected to global gene expression and unbiased lipidomic profiling. Lipid storage changes were assessed via neutral lipid staining with Oil Red O (ORO). The impact of the fatty acid synthase (FASN) inhibitor TVB-2640 on the growth and lipid storage of these cell lines was evaluated. Additionally, 13 C 2 -acetate tracing was used to examine FASN activity in parental and ET resistant cells in the absence or presence of TVB-2640.
Results: Compared to parental cells, lipid metabolism and processing pathways were notably enriched in ET resistant cells, which exhibited distinct lipidomes characterized by increased triglyceride and polyunsaturated FA (PUFA) species. ET-resistant cells displayed enhanced cytoplasmic lipid droplets. Increased FASN protein levels were observed in ET-resistant cells, and TVB-2640 effectively inhibited FASN activity. FASN inhibition reduced cell growth in some but not all cell lines and ET resistance types and did not correlate to lipid storage reduction. 13 C 2 -acetate tracing confirmed reduced palmitate synthesis and enhanced PUFA synthesis in ET-resistant cells, especially when combined with FulvR.
Conclusion: ET resistant breast cancer cells exhibit a shift towards enhanced triglyceride storage and complex lipids enriched with PUFA acyl chains. While targeting FASN alongside ET may not fully overcome ET resistance in our models, focusing on the unique lipid metabolic dependencies, such as PUFA pathways, may present a promising alternative strategy for treating ET resistant breast cancer.

DOI: https://doi.org/10.1101/2024.05.30.596684
Int J Mol Sci. 2024 May 28. pii: 5876. [Epub ahead of print]25(11):

Migratory Tumor Cells Cooperate with Cancer Associated Fibroblasts in Hormone Receptor-Positive and HER2-Negative Breast Cancer.

Eun Hye Joo, Sangmin Kim, Donghyun Park, Taeseob Lee, Woong-Yang Park, Kyung Yeon Han, Jeong Eon Lee.

  Hormone receptor-positive and HER2-negative breast cancer (HR+/HER2-BC) is the most common type with a favorable prognosis under endocrine therapy. However, it still demonstrates unpredictable progression and recurrences influenced by high tumoral diversity and microenvironmental status. To address these heterogeneous molecular characteristics of HR+/HER2-BC, we aimed to simultaneously characterize its transcriptomic landscape and genetic architecture at the same resolution. Using advanced single-cell RNA and DNA sequencing techniques together, we defined four distinct tumor subtypes. Notably, the migratory tumor subtype was closely linked to genomic alterations of EGFR, related to the tumor-promoting behavior of IL6-positive inflammatory tumor-associated fibroblast, and contributing to poor prognosis. Our study comprehensively utilizes integrated analysis to uncover the complex dynamics of this breast cancer subtype, highlighting the pivotal role of the migratory tumor subtype in influencing surrounding cells. This sheds light on potential therapeutic targets by offering enhanced insights for HR+/HER2-BC treatment.

Keywords:  CNV alteration; SIDR-seq; breast cancer; scRNA-seq; transcriptome; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms25115876
Hum Cell. 2024 Jun 16.

EP300 promotes tumor stemness via epigenetic activation of CRISP3 leading to lobaplatin resistance in triple-negative breast cancer.

Yan Wang, Yi Zhang, Xiaowei Qi.

  Lobaplatin shows antitumor activity against a wide range of tumors, including triple-negative breast cancer (TNBC), and has been linked to cancer stem cell pool. Here, we investigated the molecular mechanisms behind lobaplatin resistance and stemness in vitro and in vivo. Two chemoresistance-related GEO data sets (GSE70690 and GSE103115) were included to screen out relevant genes. Cysteine-rich secretory protein 3 (CRISP3) was found to be overexpressed in lobaplatin-resistant TNBC and related to poor diagnosis. CRISP3 expression was significantly correlated with tumor stemness markers in lobaplatin-resistant cells. E1A-associated protein p300 (EP300) regulated CRISP3 expression by affecting the H3K27ac modification of the CRISP3 promoter. In addition, knocking down EP300 curbed the malignant biological behavior of lobaplatin-resistant cells, which was antagonized by CRISP3 overexpression. Collectively, our results highlight the EP300/CRISP3 axis as a key driver of lobaplatin resistance in TNBC and suggest that therapeutic targeting of this axis may be an effective strategy for enhancing platinum sensitivity in TNBC.

Keywords:  CRISP3; EP300; Lobaplatin; Stemness; Triple-negative breast cancer

DOI:  https://doi.org/10.1007/s13577-024-01091-w
PLoS Biol. 2024 Jun;22(6): e3002666

KCNK1 promotes proliferation and metastasis of breast cancer cells by activating lactate dehydrogenase A (LDHA) and up-regulating H3K18 lactylation.

Xiangchan Hou, Jiawei Ouyang, Le Tang, Pan Wu, Xiangying Deng, Qijia Yan, Lei Shi, Songqing Fan, Chunmei Fan, Can Guo, Qianjin Liao, Yong Li, Wei Xiong, Guiyuan Li, Zhaoyang Zeng, Fuyan Wang.

Breast cancer is the most prevalent malignancy and the most significant contributor to mortality in female oncology patients. Potassium Two Pore Domain Channel Subfamily K Member 1 (KCNK1) is differentially expressed in a variety of tumors, but the mechanism of its function in breast cancer is unknown. In this study, we found for the first time that KCNK1 was significantly up-regulated in human breast cancer and was correlated with poor prognosis in breast cancer patients. KCNK1 promoted breast cancer proliferation, invasion, and metastasis in vitro and vivo. Further studies unexpectedly revealed that KCNK1 increased the glycolysis and lactate production in breast cancer cells by binding to and activating lactate dehydrogenase A (LDHA), which promoted histones lysine lactylation to induce the expression of a series of downstream genes and LDHA itself. Notably, increased expression of LDHA served as a vicious positive feedback to reduce tumor cell stiffness and adhesion, which eventually resulted in the proliferation, invasion, and metastasis of breast cancer. In conclusion, our results suggest that KCNK1 may serve as a potential breast cancer biomarker, and deeper insight into the cancer-promoting mechanism of KCNK1 may uncover a novel therapeutic target for breast cancer treatment.

DOI: https://doi.org/10.1371/journal.pbio.3002666
Histol Histopathol. 2024 May 31. 18771

TROP2 regulates cisplatin sensitivity of triple-negative breast cancer cells by regulating endoplasmic reticulum stress.

Mingqi Zhang, Jianzhong Xu, Qing Liu, Xi Yan, Ning Li.

Triple-negative breast cancer (TNBC) is a kind of breast cancer with a high metastasis rate and poor prognosis. As a transmembrane glycoprotein, tumor-associated calcium signal transducer 2 (TROP2) plays a certain role in the cancers. This study aimed to explore the potential mechanism of TROP2 affecting cisplatin (CDDP) resistance in TNBC from endoplasmic reticulum stress (ERS). MDA-MB-231 and CDDP-resistant cell lines MDA-MB-231/CDDP were used in this study, and the expression of TROP2 was detected by western blotting. After transfecting with the interference sequence of siRNA targeting TROP2, cell proliferation and apoptosis were detected by the cell counting kit-8, colony formation, and flow cytometry, and the expression of ERS-marker proteins was detected by western blotting. Furthermore, the effects of ERS in TROP2 on drug resistance of TNBC cells were explored by using ERS inhibitor 4-phenylbutyric acid (4-PBA). Results found that TROP2 expression in MDA-MB-231/CDDP was significantly upregulated compared with MDA-MB-231. The expression of TROP2 in MDA-MB-231/CDDP was significantly decreased after transfection with siRNA-TROP2, and the proliferation of MDA-MB-231 and MDA-MB-231/CDDP cells was significantly decreased after further induction with CDDP. TROP2 significantly affected TNBC cell cloning, apoptosis, and the expression of ERS-related marker proteins, while 4-PBA reversed the promoting effects of siRNA-TROP2 on apoptosis and ERS, as well as the inhibitory effects on cell proliferation, suggesting that TROP2 affected the resistance of TNBC cells to CDDP through ERS. In conclusion, TROP2 inhibited apoptosis of TNBC cells, improved the cell cloning ability, and regulated the sensitivity of TNBC cells to CDDP through ERS.

DOI: https://doi.org/10.14670/HH-18-771
Cancer Res. 2024 Jun 20.

Obesity Induces Temporally Regulated Alterations in the extracellular matrix that drive breast tumor invasion and metastasis.

Sydney J Conner, Hannah B Borges, Justinne R Guarin, Thomas J Gerton, Anna Yui, Kenneth J Salhany, Diamond N Mensah, Grace A Hamilton, Giang H Le, Katherine C Lew, Crystal Zhang, Madeleine J Oudin.

Obesity is associated with increased incidence and metastasis of triple-negative breast cancer (TNBC), an aggressive breast cancer subtype. The extracellular matrix (ECM) is a major component of the tumor microenvironment that drives metastasis. To characterize the temporal effects of age and high-fat diet-driven weight gain on the ECM, we injected allograft tumor cells at 4-week intervals into mammary fat pads of mice fed a control or high-fat diet (HFD), assessing tumor growth and metastasis and evaluating the ECM composition of the mammary fat pads, lungs, and livers. Tumor growth was increased in obese mice after 12 weeks on the HFD. Liver metastasis increased in obese mice only at 4 weeks, and elevated body weight correlated with increased metastasis to the lungs but not the liver. Whole decellularized ECM coupled with proteomics indicated that early stages of obesity were sufficient to induce changes in the ECM composition. Obesity led to increased abundance of the pro-invasive ECM proteins collagen IV and collagen VI in the mammary glands and enhanced the invasive capacity of cancer cells. Cells of stromal vascular fraction and adipose stem and progenitor cells were primarily responsible for secreting collagen IV and VI, not adipocytes. Longer exposure to HFD increased the invasive potential of ECM isolated from lung and liver, with significant changes in ECM composition found in the liver with short-term HFD exposure. Together, this data suggests that changes in the breast, lung, and liver ECM underlie some of the effects of obesity on TNBC incidence and metastasis.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-2526
Cell Rep. 2024 Jun 18. pii: S2211-1247(24)00695-8. [Epub ahead of print]43(7): 114367

Hypoxia-induced CTCF promotes EMT in breast cancer.

Parik Kakani, Shruti Ganesh Dhamdhere, Deepak Pant, Rushikesh Joshi, Jharna Mishra, Atul Samaiya, Sanjeev Shukla.

  Cancer cells experiencing hypoxic stress employ epithelial-mesenchymal transition (EMT) to undergo metastasis through rewiring of the chromatin landscape, epigenetics, and importantly, gene expression. Here, we showed that hypoxia modulates the epigenetic landscape on CTCF promoter and upregulates its expression. Hypoxia-driven epigenetic regulation, specifically DNA demethylation mediated by TET2, is a prerequisite for CTCF induction. Mechanistically, in hypoxic conditions, Hypoxia-inducible factor 1-alpha (HIF1α) binds to the unmethylated CTCF promoter, causing transcriptional upregulation. Further, we uncover the pivotal role of CTCF in promoting EMT as loss of CTCF abrogated invasiveness of hypoxic breast cancer cells. These findings highlight the functional contribution of HIF1α-CTCF axis in promoting EMT in hypoxic breast cancer cells. Lastly, CTCF expression is alleviated and the potential for EMT is diminished when the HIF1α binding is particularly disrupted through the dCas9-DNMT3A system-mediated maintenance of DNA methylation on the CTCF promoter. This axis may offer a unique therapeutic target in breast cancer.

Keywords:  CP: Cancer; CP: Molecular biology; CRISPR-dCas9-mediated editing; CTCF; EMT; breast cancer; epigenetics; hypoxia

DOI:  https://doi.org/10.1016/j.celrep.2024.114367
Cancer Lett. 2024 Jun 18. pii: S0304-3835(24)00469-5. [Epub ahead of print] 217074

FOXK2 amplification promotes breast cancer development and chemoresistance.

Yang Yu, Wen-Ming Cao, Feng Cheng, Zhongcheng Shi, Lili Han, Jinling Yi, Edaise M da Silva, Higinio Dopeso, Hui Chen, Jianhua Yang, Xiaosong Wang, Chunchao Zhang, Hong Zhang.

  Oncogene activation through DNA amplification or overexpression is a crucial driver of cancer initiation and progression. The FOXK2 gene, located on chromosome 17q25, encodes a transcription factor with a forkhead DNA-binding domain. Analysis of genomic datasets reveals that FOXK2 is frequently amplified and overexpressed in breast cancer, correlating with poor patient survival. Knockdown of FOXK2 significantly inhibited breast cancer cell proliferation, migration, anchorage-independent growth, and delayed tumor growth in a xenograft mouse model. Additionally, inhibiting FOXK2 sensitized breast cancer cells to chemotherapy. Co-overexpression of FOXK2 and mutant PI3KCA transformed non-tumorigenic MCF-10A cells, suggesting a role for FOXK2 in PI3KCA-driven tumorigenesis. CCNE2, PDK1, and ESR1 were identified as transcriptional targets of FOXK2 in MCF-7 cells. Small-molecule inhibitors of CCNE2/CDK2 (dinaciclib) and PDK1 (dichloroacetate) exhibited synergistic anti-tumor effects with PI3KCA inhibitor (alpelisib) in vitro. Inhibition of FOXK2 by dinaciclib synergistically enhanced the anti-tumor effects of alpelisib in a xenograft mouse model. Collectively, these findings highlight the oncogenic function of FOXK2 and suggest that FOXK2 and its downstream genes represent potential therapeutic targets in breast cancer.

Keywords:  Breast cancer; FOXK2; gene amplification; oncogene; transcription factor

DOI:  https://doi.org/10.1016/j.canlet.2024.217074
J Pharm Biomed Anal. 2024 Jun 05. pii: S0731-7085(24)00307-8. [Epub ahead of print]248 116267

Andrographolide targets EGFR to impede epithelial-mesenchymal transition in human breast cancer cells.

Chutima Kaewpiboon, Nawong Boonnak, Abdul-Wahab Salae, Sirichatnach Pakdeepromma, Natpaphan Yawut, Young-Hwa Chung.

  Despite the primary surgical treatment for breast cancer patients, malignant invasiveness and metastasis remain threatening factors for women with breast cancer. As chemotherapy yields unsatisfactory results, it prompted us to search for effective natural agents with few side-effects. Although andrographolide (ADGL), a natural diterpenoid lactone isolated from Andrographis paniculata, presents anticancer effects, the molecular mechanism remains unknown. Initially, on comparing the expression of proteins related to epithelial-mesenchymal transition (EMT) between nonmetastatic cancer MCF7 cells and highly metastatic cancer MDA-MB-231 cells, we found that MDA-MB-231 cells exhibit higher protein levels of N-cadherin and vimentin and lower protein levels of E-cadherin when compared to MCF7 cells. Moreover, MDA-MB-231 cells also exhibited higher EGFR expression and activity, higher STAT1 activity and abundant HDAC4 expression. To elucidate whether these proteins are closely associated with EMT, EGFR, STAT1 or HDAC4, the proteins were silenced in MDA-MB-231 breast cancer cells by their specific siRNAs. We found that silencing these proteins reduced EMT, indicating an important role of EGFR, STAT1 and HDAC4 in EMT progression. When we treated MDA-MB-231 cells with ADGL as a potential therapeutic drug, we found that ADGL treatment inhibited cell migration and invasion. Furthermore, it also recovered E-cadherin expression and decreased N-cadherin and vimentin protein levels. ADGL treatment reduced EGFR expression at a lower concentration (1 μg/mL); however, STAT1 activity and HDAC4 expression was reduced by a higher concentration (5 μg/mL) of ADGL. Moreover, we observed that the combined treatment with ADGL and siRNAs against these proteins highly sensitized the MDA-MB-231 cells to apoptosis compared to that with ADGL and control siRNA. Collectively, our results suggest that ADGL targets EGFR, thereby inhibiting EMT in human breast cancer cells.

Keywords:  Andrographolide; Breast cancer cells; EGFR; Epithelial-mesenchymal transition

DOI:  https://doi.org/10.1016/j.jpba.2024.116267