bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2024‒07‒14
fourteen papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. CDCA5 accelerates progression of breast cancer by promoting the binding of E2F1 and FOXM1.
  2. [Overexpression of CDHR2 inhibits proliferation of breast cancer cells by inhibiting the PI3K/Akt pathway].
  3. SYT7 promotes breast cancer cells growth through the PI3K/AKT pathway.
  4. Metformin Prevents Tumor Cell Growth and Invasion of Human Hormone Receptor-Positive Breast Cancer (HR+ BC) Cells via FOXA1 Inhibition.
  5. CircCFL1 Promotes TNBC Stemness and Immunoescape via Deacetylation-Mediated c-Myc Deubiquitylation to Facilitate Mutant TP53 Transcription.
  6. Hypoxic Memory Mediates Prolonged Tumor Intrinsic Type I Interferon Suppression to Promote Breast Cancer Progression.
  7. A Novel Class I HDAC Inhibitor, AW01178, Inhibits Epithelial-Mesenchymal Transition and Metastasis of Breast Cancer.
  8. Breast Cancer Cells Exhibit Mesenchymal-Epithelial Plasticity Following Dynamic Modulation of Matrix Stiffness.
  9. Resistance to FOXM1 inhibitors in breast cancer is accompanied by impeding ferroptosis and apoptotic cell death.
  10. LCP1 correlates with immune infiltration: a prognostic marker for triple-negative breast cancer.
  11. Identification of New Chemoresistance-Associated Genes in Triple-Negative Breast Cancer by Single-Cell Transcriptomic Analysis.
  12. SZC010 suppresses breast cancer development by regulating the PI3K/Akt/NF-κB signaling pathway.
  13. Astaxanthin Induces Apoptosis in MCF-7 Cells through a p53-Dependent Pathway.
  14. Cordycepin Enhances the Therapeutic Efficacy of Doxorubicin in Treating Triple-Negative Breast Cancer.
  1. J Transl Med. 2024 Jul 08. 22(1): 639
    CDCA5 accelerates progression of breast cancer by promoting the binding of E2F1 and FOXM1.
    Yiquan Xiong, Lan Shi, Lei Li, Wen Yang, Huiqiong Zhang, Xiangwang Zhao, Na Shen.
      BACKGROUND: Breast cancer is one of the most common malignant tumors in women. Cell division cycle associated 5 (CDCA5), a master regulator of sister chromatid cohesion, was reported to be upregulated in several types of cancer. Here, the function and regulation mechanism of CDCA5 in breast cancer were explored.METHODS: CDCA5 expression was identified through immunohistochemistry staining in breast cancer specimens. The correlation between CDCA5 expression with clinicopathological features and prognosis of breast cancer patients was analyzed using a tissue microarray. CDCA5 function in breast cancer was explored in CDCA5-overexpressed/knockdown cells and mice models. Co-IP, ChIP and dual-luciferase reporter assay assays were performed to clarify underlying molecular mechanisms.
    RESULTS: We found that CDCA5 was expressed at a higher level in breast cancer tissues and cell lines, and overexpression of CDCA5 was significantly associated with poor prognosis of patients with breast cancer. Moreover, CDCA5 knockdown significantly suppressed the proliferation and migration, while promoted apoptosis in vitro. Mechanistically, we revealed that CDCA5 played an important role in promoting the binding of E2F transcription factor 1 (E2F1) to the forkhead box M1 (FOXM1) promoter. Furthermore, the data of in vitro and in vivo revealed that depletion of FOXM1 alleviated the effect of CDCA5 overexpression on breast cancer. Additionally, we revealed that the Wnt/β-catenin signaling pathway was required for CDCA5 induced progression of breast cancer.
    CONCLUSIONS: We suggested that CDCA5 promoted progression of breast cancer via CDCA5/FOXM1/Wnt axis, CDCA5 might serve as a novel therapeutic target for breast cancer treatment.
    Keywords:  Breast cancer; CDCA5; FOXM1; Wnt/β-catenin signaling
    DOI:  https://doi.org/10.1186/s12967-024-05443-w
  2. Nan Fang Yi Ke Da Xue Xue Bao. 2024 Jun 20. 44(6): 1117-1125
    [Overexpression of CDHR2 inhibits proliferation of breast cancer cells by inhibiting the PI3K/Akt pathway].
    J Fang, L Liu, J Lin, F Chen.
      OBJECTIVE: To investigate the mechanism by which CDHR2 overexpression inhibits breast cancer cell growth and cell cycle pragression via the PI3K/Akt signaling pathway.METHODS: Bioinformatic analysis was performed to investigate CDHR2 expression in breast cancer and its correlation with survival outcomes of the patients. Immunohistochemistry was used to examine CDHR2 expressions in surgical specimens of tumor and adjacent tissues from 10 patients with breast cancer. CDHR2 expression levels were also detected in 5 breast cancer cell lines and a normal human mammary epithelial cell line using qRT-PCR and Western blotting. Breast cancer cell lines MDA-MB-231 and MCF7 with low CDHR2 expression were transfected with a CDHR2-overexpressing plasmid, and the changes in cell proliferation and cell cycle were evaluated using CCK-8 assay, EdU assay, and cell cycle assay; the changes in expressions of PI3K/Akt signaling pathway and cell cycle pathway proteins were detected with Western blotting.
    RESULTS: Bioinformatic analysis showed low CDHR2 expression level in both breast cancer and adjacent tissues without significant difference between them (P > 0.05), but breast cancer patients with a high expression of CDHR2 had a more favorable prognosis. Immunohistochemistry, qRT-PCR and Western blotting showed that the expression of CDHR2 was significantly down-regulated in breast cancer tissues and breast cancer cells (P < 0.01), and its overexpression strongly inhibited cell proliferation, caused cell cycle arrest, and significantly inhibited PI3K and Akt phosphorylation and the expression of cyclin D1.
    CONCLUSION: Overexpression of CDHR2 inhibits proliferation and causes cell cycle arrest in breast cancer cells possibly by inhibiting the PI3K/Akt signaling pathway.
    Keywords:  CDHR2; PI3K/Akt pathway; breast cancer; cell cycle; proliferation
    DOI:  https://doi.org/10.12122/j.issn.1673-4254.2024.06.12
  3. Transl Cancer Res. 2024 Jun 30. 13(6): 2767-2778
    SYT7 promotes breast cancer cells growth through the PI3K/AKT pathway.
    Chenghao Luo, Qingfan Mo, Guosheng Ren.
      Background: Breast cancer is one of the most malignant tumors in the reproductive system and has a poor prognosis. The aim of this study was to investigate the function and underlying mechanism of synaptotagmin 7 (SYT7) in breast cancer.Methods: We utilized The Cancer Genome Atlas (TCGA) database and the Kaplan-Meier plotter database to assess the correlation between SYT7 expression and the prognosis of breast cancer patients. The efficacy of SYT7 knockdown was evaluated through reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Furthermore, we examined the impact of SYT7 on breast cancer cell proliferation and apoptosis using Cell Counting Kit-8 (CCK-8), clone formation assays, and flow cytometry. Through Western blot analysis, we investigated the influence of SYT7 on the expression of apoptosis-related markers and the PI3K/AKT signaling pathway in breast cancer.
    Results: The TCGA database data analysis revealed a significant up-regulation of SYT7 expression in breast cancer tissues compared to normal tissues (P<0.001). A correlation was observed between SYT7 expression and tumor size (P=0.009), as well as estrogen receptor (ER) expression level (P<0.001) and progesterone receptor (PR) expression level (P<0.001) in breast cancer patients. Analysis of the Kaplan-Meier plotter database indicated that high SYT7 expression was associated with a shorter overall survival (OS) (P=0.009). The mRNA expression results indicated higher SYT7 expression in breast cancer tissues compared to adjacent normal tissues (P=0.005). CCK-8, clone formation assay, and flow cytometry results demonstrated that SYT7 promoted the proliferation and inhibited the apoptosis of breast cancer cells. Western blot assay confirmed the activation of PI3K/AKT signaling by SYT7.
    Conclusions: The findings suggest that SYT7 is highly expressed in breast cancer and that its high expression is linked to clinical characteristics and prognosis. Inhibition of SYT7 through knockdown can suppress proliferation and promote apoptosis of breast cancer cells, making it a potential target for breast cancer diagnosis and treatment.
    Keywords:  PI3K/AKT signal; Synaptotagmin 7 (SYT7); apoptosis; breast cancer; proliferation
    DOI:  https://doi.org/10.21037/tcr-24-7
  4. Int J Mol Sci. 2024 Jul 08. pii: 7494. [Epub ahead of print]25(13):
    Metformin Prevents Tumor Cell Growth and Invasion of Human Hormone Receptor-Positive Breast Cancer (HR+ BC) Cells via FOXA1 Inhibition.
    Christine Song, Dawa Jung, Ayse Tuba Kendi, Jin Kyung Rho, Eun-Joo Kim, Ian Horn, Geoffry L Curran, Sujala Ghattamaneni, Ji Yeon Shim, Pil Soo Kang, Daehun Kang, Jay B Thakkar, Sannidhi Dewan, Val J Lowe, Seung Baek Lee.
      Women with type 2 diabetes (T2D) have a higher risk of being diagnosed with breast cancer and have worse survival than non-diabetic women if they do develop breast cancer. However, more research is needed to elucidate the biological underpinnings of these relationships. Here, we found that forkhead box A1 (FOXA1), a forkhead family transcription factor, and metformin (1,1-dimethylbiguanide hydrochloride), a medication used to treat T2D, may impact hormone-receptor-positive (HR+) breast cancer (BC) tumor cell growth and metastasis. Indeed, fourteen diabetes-associated genes are highly expressed in only three HR+ breast cancer cell lines but not the other subtypes utilizing a 53,805 gene database obtained from NCBI GEO. Among the diabetes-related genes, FOXA1, MTA3, PAK4, FGFR3, and KIF22 were highly expressed in HR+ breast cancer from 4032 breast cancer patient tissue samples using the Breast Cancer Gene Expression Omnibus. Notably, elevated FOXA1 expression correlated with poorer overall survival in patients with estrogen-receptor-positive/progesterone-receptor-positive (ER+/PR+) breast cancer. Furthermore, experiments demonstrated that loss of the FOXA1 gene inhibited tumor proliferation and invasion in vitro using MCF-7 and T47D HR+ breast cancer cell lines. Metformin, an anti-diabetic medication, significantly suppressed tumor cell growth in MCF-7 cells. Additionally, either metformin treatment or FOXA1 gene deletion enhanced tamoxifen-induced tumor growth inhibition in HR+ breast cancer cell lines within an ex vivo three-dimensional (3D) organoid model. Therefore, the diabetes-related medicine metformin and FOXA1 gene inhibition might be a new treatment for patients with HR+ breast cancer when combined with tamoxifen, an endocrine therapy.
    Keywords:  forkhead box A1 (FOXA1); hormone-receptor-positive (HR+) breast cancer (BC); metastasis; metformin; tumor proliferation; type 2 diabetes (T2D)
    DOI:  https://doi.org/10.3390/ijms25137494
  5. Adv Sci (Weinh). 2024 Jul 09. e2404628
    CircCFL1 Promotes TNBC Stemness and Immunoescape via Deacetylation-Mediated c-Myc Deubiquitylation to Facilitate Mutant TP53 Transcription.
    Zekun Wang, Yaming Li, Jingwen Yang, Yuhan Sun, Yinqiao He, Yuping Wang, Yiran Liang, Xi Chen, Tong Chen, Dianwen Han, Ning Zhang, Bing Chen, Wenjing Zhao, Lijuan Wang, Dan Luo, Qifeng Yang.
      Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer. TP53, which has a mutation rate of ≈70%-80% in TNBC patients, plays oncogenic roles when mutated. However, whether circRNAs can exert their effects on TNBC through regulating mutant TP53 has not been well evaluated. In this study, circCFL1, which is highly expressed in TNBC cells and tissues and has prognostic potential is identified. Functionally, circCFL1 promoted the proliferation, metastasis and stemness of TNBC cells. Mechanistically, circCFL1 acted as a scaffold to enhance the interaction between HDAC1 and c-Myc, further promoting the stability of c-Myc via deacetylation-mediated inhibition of K48-linked ubiquitylation. Stably expressed c-Myc further enhanced the expression of mutp53 in TNBC cells with TP53 mutations by directly binding to the promoter of TP53, which promoted the stemness of TNBC cells via activation of the p-AKT/WIP/YAP/TAZ pathway. Moreover, circCFL1 can facilitate the immune escape of TNBC cells by promoting the expression of PD-L1 and suppressing the antitumor immunity of CD8+ T cells. In conclusion, the results revealed that circCFL1 plays an oncogenic role by promoting the HDAC1/c-Myc/mutp53 axis, which can serve as a potential diagnostic biomarker and therapeutic target for TNBC patients with TP53 mutations.
    Keywords:  TNBC; circular RNA; immune escape; mutant TP53; stemness
    DOI:  https://doi.org/10.1002/advs.202404628
  6. Cancer Res. 2024 Jul 11.
    Hypoxic Memory Mediates Prolonged Tumor Intrinsic Type I Interferon Suppression to Promote Breast Cancer Progression.
    Oihana Iriondo, Desirea Mecenas, Yilin Li, Christopher R Chin, Amal Thomas, Aidan Moriarty, Rebecca Marker, Yiru Jess Wang, Haley Hendrick, Yonatan Amzaleg, Veronica Ortiz, Matthew MacKay, Amber Dickerson, Grace Lee, Sevana Harotoonian, Bérénice A Benayoun, Andrew Smith, Christopher E Mason, Evanthia T Roussos Torres, Remi Klotz, Min Yu.
      Hypoxia is a common feature of many solid tumors due to aberrant proliferation and angiogenesis that is associated with tumor progression and metastasis. Most of the well-known hypoxia effects are mediated through hypoxia-inducible factors (HIFs). Identification of the long-lasting effects of hypoxia beyond the immediate HIF-induced alterations could provide a better understanding of hypoxia-driven metastasis and potential strategies to circumvent it. Here, we uncovered a hypoxia-induced mechanism that exerts a prolonged effect to promote metastasis. In breast cancer patient-derived circulating tumor cell (CTC) lines and common breast cancer cell lines, hypoxia downregulated tumor intrinsic type I interferon (IFN) signaling and its downstream antigen presentation (AP) machinery in luminal breast cancer cells, via both HIF-dependent and HIF-independent mechanisms. Hypoxia induced durable IFN/AP suppression in certain cell types that was sustained after returning to normoxic conditions, presenting a "hypoxic memory" phenotype. Hypoxic memory of IFN/AP downregulation was established by specific hypoxic priming, and cells with hypoxic memory had an enhanced ability for tumorigenesis and metastasis. Overexpression of IRF3 enhanced IFN signaling and reduced tumor growth in normoxic, but not hypoxic, conditions. The histone deacetylase inhibitor (HDACi) entinostat upregulated IFN targets and erased the hypoxic memory. These results point to a mechanism by which hypoxia facilitates tumor progression through a long-lasting memory that provides advantages for CTCs during the metastatic cascade.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-2028
  7. Int J Mol Sci. 2024 Jun 30. pii: 7234. [Epub ahead of print]25(13):
    A Novel Class I HDAC Inhibitor, AW01178, Inhibits Epithelial-Mesenchymal Transition and Metastasis of Breast Cancer.
    Xiangxiang Liu, Yawen Chen, Yang Li, Ying Shen, Shasha Dong, Jiang Tan.
      Epithelial-mesenchymal transition (EMT) refers to the transformation of polar epithelial cells into motile mesenchymal cells under specific physiological or pathological conditions, thus promoting the metastasis of cancer cells. Epithelial cadherin (E-cadherin) is a protein that plays an important role in the acquisition of tumor cell motility and serves as a key EMT epithelial marker. In the present study, AW01178, a small-molecule compound with potential therapeutic efficacy, was identified via in-cell Western high-throughput screening technology using E-cadherin as the target. The compound induced the upregulation of E-cadherin at both mRNA and protein levels and inhibited the EMT of breast cancer cells in vitro as well as metastasis in vivo. Mechanistically, AW01178 is a novel benzacetamide histone deacetylase inhibitor (HDACi) mainly targeting class I histone deacetylases. AW01178 promoted the transcription and expression of E-cadherin through enhancing the acetylation level of histone H3 in the E-cadherin promoter region, thereby inhibiting the metastasis of breast cancer cells. The collective findings support the potential utility of the novel HDACi compound identified in this study, AW01178, as a therapeutic drug for breast cancer and highlight its value for the future development of HDACi structures as anticancer drugs.
    Keywords:  AW01178; HDACi; breast cancer; metastasis
    DOI:  https://doi.org/10.3390/ijms25137234
  8. Adv Biol (Weinh). 2024 Jul 08. e2400087
    Breast Cancer Cells Exhibit Mesenchymal-Epithelial Plasticity Following Dynamic Modulation of Matrix Stiffness.
    Chinmay S Sankhe, Jessica L Sacco, Jacob Lawton, Ryan A Fair, David Vidotto Rezende Soares, Mohammed K R Aldahdooh, Enrique D Gomez, Esther W Gomez.
      Mesenchymal-epithelial transition (MET) is essential for tissue and organ development and is thought to contribute to cancer by enabling the establishment of metastatic lesions. Despite its importance in both health and disease, there is a lack of in vitro platforms to study MET and little is known about the regulation of MET by mechanical cues. Here, hyaluronic acid-based hydrogels with dynamic and tunable stiffnesses mimicking that of normal and tumorigenic mammary tissue are synthesized. The platform is then utilized to examine the response of mammary epithelial cells and breast cancer cells to dynamic modulation of matrix stiffness. Gradual softening of the hydrogels reduces proliferation and increases apoptosis of breast cancer cells. Moreover, breast cancer cells exhibit temporal changes in cell morphology, cytoskeletal organization, and gene expression that are consistent with mesenchymal-epithelial plasticity as the stiffness of the matrix is reduced. A reduction in matrix stiffness attenuates the expression of integrin-linked kinase, and inhibition of integrin-linked kinase impacts proliferation, apoptosis, and gene expression in cells cultured on stiff and dynamic hydrogels. Overall, these findings reveal intermediate epithelial/mesenchymal states as cells move along a matrix stiffness-mediated MET trajectory and suggest an important role for matrix mechanics in regulating mesenchymal-epithelial plasticity.
    Keywords:  apoptosis; breast cancer; extracellular matrix; hyaluronic acid; integrin‐linked kinase
    DOI:  https://doi.org/10.1002/adbi.202400087
  9. Breast Cancer Res Treat. 2024 Jul 09.
    Resistance to FOXM1 inhibitors in breast cancer is accompanied by impeding ferroptosis and apoptotic cell death.
    Sandeep Kumar, Yvonne Ziegler, Blake N Plotner, Kristen M Flatt, Sung Hoon Kim, John A Katzenellenbogen, Benita S Katzenellenbogen.
      PURPOSE: Cancer treatments often become ineffective because of acquired drug resistance. To characterize changes in breast cancer cells accompanying development of resistance to inhibitors of the oncogenic transcription factor, FOXM1, we investigated the suppression of cell death pathways, especially ferroptosis, in FOXM1 inhibitor-resistant cells. We also explored whether ferroptosis activators can synergize with FOXM1 inhibitors and can overcome FOXM1 inhibitor resistance.METHODS: In estrogen receptor-positive and triple-negative breast cancer cells treated with FOXM1 inhibitor NB73 and ferroptosis activators dihydroartemisinin and JKE1674, alone and in combination, we measured suppression of cell viability, motility, and colony formation, and monitored changes in gene and protein pathway expressions and mitochondrial integrity.
    RESULTS: Growth suppression of breast cancer cells by FOXM1 inhibitors is accompanied by increased cell death and alterations in mitochondrial morphology and metabolic activity. Low doses of FOXM1 inhibitor strongly synergize with ferroptosis inducers to reduce cell viability, migration, colony formation, and expression of proliferation-related genes, and increase intracellular Fe+2 and lipid peroxidation, markers of ferroptosis. Acquired resistance to FOXM1 inhibition is associated with increased expression of cancer stem-cell markers and proteins that repress ferroptosis, enabling cell survival and drug resistance. Notably, resistant cells are still sensitive to growth suppression by low doses of ferroptosis activators, effectively overcoming the acquired resistance.
    CONCLUSION: Delineating changes in viability and cell death pathways that can overcome drug resistance should be helpful in determining approaches that might best prevent or reverse resistance to therapeutic targeting of FOXM1 and ultimately improve patient clinical outcomes.
    Keywords:  Drug resistance; Estrogen receptor; FOXM1; Ferroptosis; Gene expression; Proliferation
    DOI:  https://doi.org/10.1007/s10549-024-07420-9
  10. BMC Immunol. 2024 Jul 08. 25(1): 42
    LCP1 correlates with immune infiltration: a prognostic marker for triple-negative breast cancer.
    Shuaikang Pan, Mengting Wan, Hongwei Jin, Ran Ning, Jinguo Zhang, Xinghua Han.
      OBJECTIVE: Triple-Negative Breast Cancer (TNBC) is known for its aggressiveness and treatment challenges due to the absence of ER, PR, and HER2 receptors. Our work emphasizes the prognostic value of LCP1 (Lymphocyte cytosolic protein 1), which plays a crucial role in cell processes and immune cell activity, to predict outcomes and guide treatments in TNBC.METHODS: We explored LCP1 as a potential biomarker in TNBC and investigated the mRNA and protein expression levels of LCP1. We investigated different databases, including GTEX, TCGA, GEO, cBioPortal and Kaplan-Meier Plotter. Immunohistochemistry on TNBC and benign tumor samples was performed to examine LCP1's relationship with patient clinical characteristics and macrophage markers. We also assessed survival rates, immune cell infiltration, and drug sensitivity related to LCP1 using various bioinformatics tools.
    RESULTS: The results indicated that LCP1 expression was higher in TNBC tissues compared to adjacent normal tissues. However, high expression of LCP1 was significantly associated with favorable survival outcomes in patients with TNBC. Enrichment analysis revealed that genes co-expressed with LCP1 were significantly enriched in various immune processes. LCP1 showed a positive correlation with the infiltration of resting dendritic cells, M1 macrophages, and memory CD4 T cells, and a negative correlation with M2 macrophages. Further analysis suggested a link between high levels of LCP1 and increased survival outcomes in cancer patients receiving immunotherapy.
    CONCLUSION: LCP1 may serve as a potential diagnostic and prognostic biomarker for TNBC, which was closely associated with immune cell infiltration, particularly M1 and M2 macrophages. Our findings may provide valuable insights into immunotherapeutic strategies for TNBC patients.
    Keywords:  Biomarker; Immune infiltrate; LCP1; Prognostic; Triple-negative breast cancer
    DOI:  https://doi.org/10.1186/s12865-024-00635-x
  11. Int J Mol Sci. 2024 Jun 22. pii: 6853. [Epub ahead of print]25(13):
    Identification of New Chemoresistance-Associated Genes in Triple-Negative Breast Cancer by Single-Cell Transcriptomic Analysis.
    Spyros Foutadakis, Dimitrios Kordias, Giannis Vatsellas, Angeliki Magklara.
      Triple-negative breast cancer (TNBC) is a particularly aggressive mammary neoplasia with a high fatality rate, mainly because of the development of resistance to administered chemotherapy, the standard treatment for this disease. In this study, we employ both bulk RNA-sequencing and single-cell RNA-sequencing (scRNA-seq) to investigate the transcriptional landscape of TNBC cells cultured in two-dimensional monolayers or three-dimensional spheroids, before and after developing resistance to the chemotherapeutic agents paclitaxel and doxorubicin. Our findings reveal significant transcriptional heterogeneity within the TNBC cell populations, with the scRNA-seq identifying rare subsets of cells that express resistance-associated genes not detected by the bulk RNA-seq. Furthermore, we observe a partial shift towards a highly mesenchymal phenotype in chemoresistant cells, suggesting the epithelial-to-mesenchymal transition (EMT) as a prevalent mechanism of resistance in subgroups of these cells. These insights highlight potential therapeutic targets, such as the PDGF signaling pathway mediating EMT, which could be exploited in this setting. Our study underscores the importance of single-cell approaches in understanding tumor heterogeneity and developing more effective, personalized treatment strategies to overcome chemoresistance in TNBC.
    Keywords:  3D spheroids; bulk RNA-sequencing; chemoresistance; single-cell RNA-sequencing; transcriptomics; triple-negative breast cancer
    DOI:  https://doi.org/10.3390/ijms25136853
  12. Chin Clin Oncol. 2024 Jun;13(3): 34
    SZC010 suppresses breast cancer development by regulating the PI3K/Akt/NF-κB signaling pathway.
    Junhan Jiang, Xiaorui Li, Hongtao Xu, Yiwen Ma, Meiyi Fu, Xiangyu Guo, Tao Sun, Xinyu Zheng.
      BACKGROUND: Breast cancer has become one of the leading causes of cancer deaths and is the most frequently diagnosed cancer among females worldwide. Despite advances in breast cancer therapy, metastatic disease in most patients will eventually progress due to the development of de novo or secondary resistance. Thus, it is extremely important to seek novel drugs with high effectiveness and low toxicity for systematic therapy.METHODS: We applied a 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in this study to analyze and evaluate the cytotoxic activity of oleanolic acid (OA) and its derivatives in three types of breast cancer cell lines (MDA-MB-231, MCF-7, and MDA-MB-453). A flow cytometry assay was performed to access the mechanisms of apoptosis and cell cycle analysis in SZC010 in MDA-MB-453 cells. Apoptosis- and cyclin-related proteins were evaluated by western blot. The key proteins of the NF-κB and PI3K-Akt-mTOR signaling pathway were also evaluated by western blot.
    RESULTS: Our results revealed that all OA derivatives were more effective than OA in three types of breast cancer cell lines (MCF-7, MDA-MB-231, and MDA-MB-453). Among these seven OA derivatives, SZC010 exhibited the most potent cytotoxicity in MDA-MB-453 cells. Additionally, we observed that SZC010 treatment induced dose-and time-dependent growth inhibition in MDA-MB-453 cells. Furthermore, we demonstrated that SZC010 induced growth arrest in the G2/M phase and apoptosis by inhibition of NF-κB activation via the PI3K/Akt/mTOR signaling pathway.
    CONCLUSIONS: Our data indicate that the novel OA derivative, SZC010, has great potential in breast cancer therapy.
    Keywords:  NF-κB; Oleanolic acid (OA); PI3K/Akt/mTOR signaling pathway; apoptosis; breast cancer cells
    DOI:  https://doi.org/10.21037/cco-24-10
  13. Int J Mol Sci. 2024 Jun 28. pii: 7111. [Epub ahead of print]25(13):
    Astaxanthin Induces Apoptosis in MCF-7 Cells through a p53-Dependent Pathway.
    Koanhoi Kim, Hyok-Rae Cho, Yonghae Son.
      Astaxanthin (3,3'-dihydroxy-β,β-carotene-4,4'-dione; AXT) is a xanthophyll β-carotenoid found in microalgae, seafood, fungi, complex plants, flamingos, and quail. It is well known that AXT plays a role as a drug with antioxidant and antitumor properties. Furthermore, several studies have reported that the reagent shows anti-inflammatory and neuroprotective effects. Recently, it was found that AXT acts as a peroxisome proliferator-activated receptor γ (PPARγ) modulator. To investigate the effect of AXT on MCF-7 cells (a human breast cancer cell line), the cells were treated with various concentrations of AXT. The treatment induced the decrease in cell number in a dose-dependent manner. Additionally, the Annexin V-positive cells were increased by the AXT treatment. These results indicated that apoptosis was induced in the tumor cells through the treatment of AXT. To elucidate the connection between apoptosis and p53, the levels of p53 and p21 proteins were assessed. Consequently, it was observed that the expression of p53 and p21 increased proportionally to the concentration of the AXT treatment. These findings suggest that the apoptosis of MCF-7 cells induced by AXT operates through a p53-dependent pathway, implying that AXT could potentially have a beneficial role in future breast cancer treatments. Thus, our results will provide a direction for future cancer challenges.
    Keywords:  MCF-7; apoptosis; astaxanthin; breast cancer; p53
    DOI:  https://doi.org/10.3390/ijms25137111
  14. Int J Mol Sci. 2024 Jun 27. pii: 7077. [Epub ahead of print]25(13):
    Cordycepin Enhances the Therapeutic Efficacy of Doxorubicin in Treating Triple-Negative Breast Cancer.
    Haichen Huang, Xiaomin Li, Wenya Wu, Chengyi Liu, Yunhe Shao, Xiaoping Wu, Junsheng Fu.
      Triple-negative breast cancer (TNBC) is a subtype of breast cancer with high mortality and poor prognosis. Meanwhile, doxorubicin, a chemotherapeutic agent for triple-negative breast cancer, has poor sensitivity. The objective of this study was to examine the effect of cordycepin on doxorubicin sensitivity and efficacy in the TNBC xenograft model and explore the relevant molecular pathways. The combination of the drugs in nude mice carrying MDA-MB-231 xenografts significantly reduced the volume, size, and weight of xenografts and improved the tumor inhibition rate. The drug combination was significantly more effective than cordycepin or doxorubicin alone, reflecting the fact that cordycepin enhanced the anti-tumor effects of doxorubicin in MDA-MB-231 xenografts. At the same time, the monitoring of several biological parameters failed to detect any obvious side effects associated with this treatment. After predicting the importance of the TNF pathway in inhibiting tumor growth using network pharmacology methods, we verified the expression of TNF pathway targets via immunohistochemistry and quantitative PCR. Furthermore, a TNF-α inhibitor was able to abrogate the beneficial effects of cordycepin and doxorubicin treatment in MDA-MB-231 cells. This clearly indicates the role of TNF-α, or related molecules, in mediating the therapeutic benefits of the combined treatment in animals carrying TNBC xenografts. The observations reported here may present a new direction for the clinical treatment of TNBC.
    Keywords:  TNF signaling pathway; cordycepin; doxorubicin; network pharmacology; triple-negative breast cancer
    DOI:  https://doi.org/10.3390/ijms25137077
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