bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2025–01–05
nine papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. T cell induced expression of Coronin-1A facilitates blood-brain barrier transmigration of breast cancer cells.
  2. FOSL1 transcriptionally dictates the Warburg effect and enhances chemoresistance in triple-negative breast cancer.
  3. MiR-363-3p induces tamoxifen resistance in breast cancer cells through PTEN modulation.
  4. Endocrine-targeting therapies shift the breast microbiome to reduce estrogen receptor-α breast cancer risk.
  5. Oncogenic HJURP enhancer promotes the aggressive behavior of triple-negative breast cancer in association with p53/E2F1/FOXM1-axis.
  6. L3MBTL3 and STAT3 collaboratively upregulate SNAIL expression to promote metastasis in female breast cancer.
  7. Adipose MSCs response to breast cancer cell-derived factors in conditioned media and extracts.
  8. GRK6 palmitoylation dictates triple-negative breast cancer metastasis via recruiting the β-Arrestin 2/MAPKs/NF-κB signaling axis.
  9. FGFR2-RUNX2 activation: An unexplored therapeutic pathway in luminal breast cancer related to tumor progression.
  1. Sci Rep. 2024 Dec 28. 14(1): 31516
    T cell induced expression of Coronin-1A facilitates blood-brain barrier transmigration of breast cancer cells.
    Johan M Kros, Lona Zeneyedpour, Rute M S M Pedrosa, Zineb Belcaid, Willem A Dik, Theo M Luider, Dana A M Mustafa.
      In previous work we discovered that T lymphocytes play a prominent role in the rise of brain metastases of ER-negative breast cancers. In the present study we explored how T lymphocytes promote breast cancer cell penetration through the blood brain barrier (BBB). An in vitro BBB model was employed to study the effects of T lymphocytes on BBB trespassing capacity of three different breast carcinoma cell lines. Differential protein expression was explored by comparing the proteomes of the breast cancer cells before and after co-culture with activated T lymphocytes using liquid chromatography-mass spectrometry (LC-MS). siRNA was used to silence protein expression in the breast cancer cells to study contribution to in vitro BBB passage. Furthermore, protein expression in primary breast cancer tissues was explored and related to brain-metastatic potential. Co-culturing with activated T lymphocytes or their conditioned medium (CM) resulted in increased passage through the in vitro BBB. The effects were less for cell line MDA-MB-231-B2M2 (brain affinity) as compared to MDA-MB-231 and SK-BR-7. Mass spectrometry-based proteomics revealed significant alterations in the expression of 35 proteins by the breast cancer cell lines upon T cell contact. Among the proteins is coronin-1 A, a protein related to cell motility. Knockdown of CORO1A in the breast cancer cells reduced their ability to cross the artificial BBB to 60%. The effects were significantly less for the cell line derived from breast cancer with affinity for brain. The expression of coronin-1A was confirmed by immunohistochemistry and RT-PCR of 52 breast cancer samples of patients with metastasized breast cancers, with and without brain locations. Lastly, CORO1A upregulation was validated in a publicly available mRNA expression database from 204 primary breast cancers with known metastatic sites. We conclude that T lymphocytes trigger cancer cells to express proteins including coronin-1A that enable the cancer cells to cross an in vitro BBB. In addition, a prominent role of coronin-1A in the formation of cerebral metastases in breast cancer patients is strongly suggestive by its upregulation in tissue samples of breast cancer patients with brain metastases.
    Keywords:  Blood–brain barrier; Brain metastasis; Breast cancer; Coronin-1A; Liquid chromatography-mass spectrometry; Proteomics
    DOI:  https://doi.org/10.1038/s41598-024-83301-x
  2. J Transl Med. 2025 Jan 02. 23(1): 1
    FOSL1 transcriptionally dictates the Warburg effect and enhances chemoresistance in triple-negative breast cancer.
    Gang Zhao, Yutong Liu, Shiqi Yin, Runxiang Cao, Qian Zhao, Yifan Fu, Ye Du.
       BACKGROUND: Dysregulated energy metabolism has emerged as a defining hallmark of cancer, particularly evident in triple-negative breast cancer (TNBC). Distinct from other breast cancer subtypes, TNBC exhibits heightened glycolysis and aggressiveness. However, the transcriptional mechanisms of aerobic glycolysis in TNBC remains poorly understood.
    METHODS: The Cancer Genome Atlas (TCGA) cohort was utilized to identify genes associated with glycolysis. The role of FOSL1 in glycolysis and tumor growth in TNBC cells was confirmed through both loss-of-function and gain-of-function experiments. The subcutaneous xenograft model was established to evaluate the therapeutic potential of targeting FOSL1 in TNBC. Additionally, chromatin immunoprecipitation and luciferase reporter assays were employed to investigate the transcriptional regulation of glycolytic genes mediated by FOSL1.
    RESULTS: FOSL1 is identified as a pivotal glycolysis-related transcription factor in TNBC. Functional verification shows that FOSL1 enhances the glycolytic metabolism of TNBC cells, as evidenced by glucose uptake, lactate production, and extracellular acidification rates. Notably, FOSL1 promotes tumor growth in TNBC in a glycolysis-dependent manner, as inhibiting glycolysis with 2-Deoxy-D-glucose markedly diminishes the oncogenic effects of FOSL1 in TNBC. Mechanistically, FOSL1 transcriptionally activates the expression of genes such as SLC2A1, ENO1, and LDHA, which further accelerate the glycolytic flux. Moreover, FOSL1 is highly expressed in doxorubicin (DOX)-resistant TNBC cells and clinical samples from cases of progressive disease following neoadjuvant chemotherapy. Targeting FOSL1 proves effective in overcoming chemoresistance in DOX-resistant MDA-MB-231 cells.
    CONCLUSION: In summary, FOSL1 establishes a robust link between aerobic glycolysis and carcinogenesis, positioning it as a promising therapeutic target, especially in the context of TNBC chemotherapy.
    Keywords:  Drug resistance; Energy metabolism; Gene promoter; Glucose metabolism; Glucose transporter
    DOI:  https://doi.org/10.1186/s12967-024-06014-9
  3. Sci Rep. 2024 Dec 30. 14(1): 32135
    MiR-363-3p induces tamoxifen resistance in breast cancer cells through PTEN modulation.
    Yaning Liang, Cuiyu Shi, Yu Wang, Bingjie Fan, Wei Song, Rong Shen.
      Nowadays, the investigation for overcoming tamoxifen (TAM) resistance is confronting a considerable challenge. Therefore, immediate attention is required to elucidate the mechanism underlying TAM resistance in breast cancer. This research primarily aimed to define how miRNA-363-3p facilitates resistance to TAM in breast cancer. High-throughput miRNA sequencing was performed using RNAs prepared from breast cancer MCF-7 cells and TAM-resistant MCF-7 cells (MCF-7-TAM). An increase in miRNA-363-3p levels was observed in MCF-7-TAM cells. In MCF-7 cells, miRNA-363-3p directly targeted and negatively regulated phosphatase and tensin homolog (PTEN). Reduction of miRNA-363-3p retarded cell growth and accelerated cell apoptosis, thereby enhancing the sensitivity of TAM. Moreover, analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway showed significant enrichment of target genes within the phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. Ultimately, miR-363-3p decreased the responsiveness of breast cancer cells to TAM by targeting and suppressing PTEN through a mechanism associated with the PI3K-Akt pathway. Therefore, these results suggest that miR-363-3p-dependent PTEN expression contributes to the mechanisms underlying breast cancer endocrine resistance.
    Keywords:  Breast cancer; Hsa-miR-363-3p; PI3K/AKT signaling pathway; PTEN; TAM resistance
    DOI:  https://doi.org/10.1038/s41598-024-83938-8
  4. Cell Rep Med. 2024 Dec 26. pii: S2666-3791(24)00651-7. [Epub ahead of print] 101880
    Endocrine-targeting therapies shift the breast microbiome to reduce estrogen receptor-α breast cancer risk.
    Alana A Arnone, Yu-Ting Tsai, J Mark Cline, Adam S Wilson, Brian Westwood, Meghan E Seger, Akiko Chiba, Marissa Howard-McNatt, Edward A Levine, Alexandra Thomas, David R Soto-Pantoja, Katherine L Cook.
      Studies indicate that breast tissue has a distinct modifiable microbiome population. We demonstrate that endocrine-targeting therapies, such as tamoxifen, reshape the non-cancerous breast microbiome to influence tissue metabolism and reduce tumorigenesis. Using 16S sequencing, we found that tamoxifen alters β-diversity and increases Firmicutes abundance, including Lactobacillus spp., in mammary glands (MGs) of mice and non-human primates. Immunohistochemistry showed that lipoteichoic acid (LTA)-positive bacteria were elevated in tamoxifen-treated breast tissue. In B6.MMTV-PyMT mice, intra-nipple probiotic bacteria injections reduced tumorigenesis, altered metabolic gene expression, and decreased tumor proliferation. Probiotic-conditioned media selectively reduced viability in estrogen receptor-positive (ER+) breast cancer cells and altered mitochondrial metabolism in non-cancerous epithelial cells. Human tumor samples revealed that LTA-positive bacteria negatively correlated with Ki67, suggesting that endocrine therapies influence tumor-associated microbiota to regulate proliferation. Our data indicate that endocrine-targeting therapies modify the breast microbiome, corresponding with a shift in tissue metabolism to potentially reduce ER+ breast cancer risk.
    Keywords:  Lactobacillus; MMTV-PyMT mice; Streptococcus; aromatase inhibitors; breast cancer; diet; estrogen receptor; faslodex; glycolysis; metabolism; microbiome; prevention; tamoxifen
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101880
  5. Cancer Lett. 2024 Dec 28. pii: S0304-3835(24)00818-8. [Epub ahead of print] 217423
    Oncogenic HJURP enhancer promotes the aggressive behavior of triple-negative breast cancer in association with p53/E2F1/FOXM1-axis.
    Yunlu Jia, Yongxia Chen, Ming Chen, Mengye He, Suzhen Xu, Han Li, Xuanyi Lin, Linbo Wang, Jichun Zhou, Peng Shen, Xiao Luo, Xiaochen Zhang, Jian Ruan.
      Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer, lacking effective targeted therapies and presenting with a poor prognosis. In this study, we utilized the epigenomic landscape, TCGA database, and clinical samples to uncover the pivotal role of HJURP in TNBC. Our investigation revealed a strong correlation between elevated HJURP expression and unfavorable prognosis, metastatic progression, and late-stage of breast cancer. RNA-seq analysis indicated that HJURP silencing suppressed transcriptional signatures associated with malignant phenotypes of TNBC, thereby inhibiting cell proliferation, migration, invasion, epithelial-to-mesenchymal transition (EMT), and promoting apoptosis. Knockdown of HJURP impaired the growth of MDA-MB231-engrafted tumors, reducing KI67 and HJURP expression in the shHJURP group. Publicly available datasets showed differential expression of HJURP in TNBC cells harboring mutant p53 (mutp53) compared to those with wild-type p53 (wtp53), highlighting a potential mechanism underlying TNBC's aggressiveness. Mechanistically, we established that loss or mutation of wtp53 enhances HJURP expression, whereas wtp53 accumulation restrains HJURP transcription. We elucidated a regulatory axis where wtp53 positively modulates the transcription factors FOXM1 and E2F1, which form a complex with H3K27ac to bind preferentially to the HJURP enhancer, driving its transcription. CRISPR interference targeting the enhancer region resulted in diminished HJURP expression and phenotypes reminiscent of HJURP knockdown, accompanied by reduced binding of E2F1, FOXM1, and H3K27ac to the enhancer. In a translational perspective, we found marked decreases in survival of breast cancer patients expressing high HJURP levels carrying wtp53. Collectively, our findings identify enhancer-driven HJURP as a pivotal molecular bypass that suppresses the tumor-suppressive and pro-apoptotic effects of wtp53. Targeting HJURP presents a compelling therapeutic strategy to inhibit tumor proliferation, metastasis, and invasiveness specifically p53-mutant TNBC.
    Keywords:  E2F1; Enhancers; FOXM1; HJURP; TNBC; p53
    DOI:  https://doi.org/10.1016/j.canlet.2024.217423
  6. Nat Commun. 2025 Jan 02. 16(1): 231
    L3MBTL3 and STAT3 collaboratively upregulate SNAIL expression to promote metastasis in female breast cancer.
    Jianpeng Xiao, Jie Wang, Jialun Li, Jie Xiao, CuiCui Liu, Libi Tan, Yanhong Tu, Ruifang Yang, Yujie Pei, Minghua Wang, Jiemin Wong, Binhua P Zhou, Jing Li, Jing Feng.
      The STAT3 pathway promotes epithelial-mesenchymal transition, migration, invasion and metastasis in cancer. STAT3 upregulates the transcription of the key epithelial-mesenchymal transition transcription factor SNAIL in a DNA binding-independent manner. However, the mechanism by which STAT3 is recruited to the SNAIL promoter to upregulate its expression is still elusive. In our study, the lysine methylation binding protein L3MBTL3 is positively associated with metastasis and poor prognosis in female patients with breast cancer. L3MBTL3 also promotes epithelial-mesenchymal transition and metastasis in breast cancer. Mechanistic analysis reveals that L3MBTL3 interacts with STAT3 and recruits STAT3 to the SNAIL promoter to increase SNAIL transcription levels. The interaction between L3MBTL3 and STAT3 is required for SNAIL transcription upregulation and metastasis in breast cancer, while the methylated lysine binding activity of L3MBTL3 is not required for these functions. In conclusion, L3MBTL3 and STAT3 synergistically upregulate SNAIL expression to promote breast cancer metastasis.
    DOI:  https://doi.org/10.1038/s41467-024-55617-9
  7. Cell Tissue Bank. 2024 Dec 29. 26(1): 6
    Adipose MSCs response to breast cancer cell-derived factors in conditioned media and extracts.
    Fatemeh Sadeghian, Faezeh Kazemi, Ali Pirsadeghi, Fatemeh Asadi, Mahnaz Tashakori, Aliakbar Yousefi-Ahmadipour.
      Interactions between MSCs and cancer cells are complex and multifaceted and have been shown to exhibit both pro-tumor and antitumor effects. This study investigated the effects of conditioned medium (CM) and cell extract (CE) from two different ERα statuses, MCF-7 and MDA-MB-231 breast cancer cell lines, on adipose-derived mesenchymal stem cells (ASCs). Findings showed that CM and CE increased cellular metabolic activity and viability of ASCs, upregulated angiogenic factors VEGF and HIF-1α, and cytokine TGF-β expression levels. However, CM and CE treatment did not significantly affect the clonogenicity of ASCs. In addition, apoptosis-related genes caspase-3 and 9 showed differential expression patterns among the treatment groups. The findings suggest that breast cancer cell-derived factors can modulate the behavior of ASCs, highlighting their potential as a therapeutic tool in breast cancer treatment and tissue regeneration. However, it is essential to consider the potential risks associated with CM and CE treatment on ASCs, as well as the potential recruitment of ASCs by cancer tumors and the risks associated with this recruitment. Further research is needed to elucidate these potential risks and benefits.
    Keywords:  Breast cancer cells; Cell extract; Conditioned medium; MSCs; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s10561-024-10156-x
  8. Breast Cancer Res. 2024 Dec 31. 26(1): 193
    GRK6 palmitoylation dictates triple-negative breast cancer metastasis via recruiting the β-Arrestin 2/MAPKs/NF-κB signaling axis.
    Wen-Ke Wang, Hui-Yu Lin, Che-Hsuan Lin, Hsun-Hua Lee, Yen-Lin Chen, Yu-Hsien Kent Lin, Hui-Wen Chiu, Shry-Ming Sheen-Chen, Yuan-Feng Lin.
       BACKGROUND: Triple negative breast cancer (TNBC) belongs to the worst prognosis of breast cancer subtype probably because of distant metastasis to other organs, e.g. lungs. However, the mechanism underlying TNBC metastasis remains largely unknown.
    METHODS: Bioinformatics analysis was conducted to evaluate the mRNA/protein expression and prognostic significance of G protein-coupled receptor kinase 6 (GRK6) in BC subtypes. RT-PCR assays were used to test the GRK6 expression in human BC tissues and cell lines. The in vitro cellular migration and in vivo lung colony-forming assays were established to estimate the metastatic potentials of TNBC cells. Western blotting was employed to examine protein phosphorylation, translocation and expression in the designed experiments.
    RESULTS: Here we show that GRK6 upregulation is extensively detected in TNBC compared to normal mammary tissues and other BC subtypes and correlates with an increased risk for distant metastasis in TNBC patients. GRK6 knockdown suppressed but overexpression potentiated the cellular migration and lung colony-forming abilities of TNBC cells. Moreover, our data demonstrated that the posttranslational palmitoylation of GRK6 is extremely critical for activating β-Arrestin 2/mitogen-activated protein kinases (MAPKs)/NF-κB signaling axis and fostering the metastatic potentials of TNBC cells. Accordingly, the pharmaceutical inhibition of GRK6 kinase activity dramatically suppressed the activation of β-Arrestin 2, MAPKs and NF-κB and the cellular migration ability of highly metastatic MDA-MB231 cells. Sequentially blocking the β-Arrestin 2/MAPKs/NF-κB axis with their inhibitors predominantly mitigated the GRK6-promoted migration ability of poorly metastatic HCC1937 cells.
    CONCLUSION: Our results not only provide a novel mechanism for TNBC metastasis but also offer a new therapeutic strategy to combat metastatic TNBC via targeting GRK6 activity.
    Keywords:  GRK6; MAPKs; Metastasis; NF-κB; Triple-negative breast cancer; β-Arrestin 2
    DOI:  https://doi.org/10.1186/s13058-024-01953-z
  9. Int J Cancer. 2024 Dec 28.
    FGFR2-RUNX2 activation: An unexplored therapeutic pathway in luminal breast cancer related to tumor progression.
    María S Rodriguez, Yamil D Mahmoud, Silvia Vanzulli, Sebastián Giulianelli, Eunice Spengler, Paula Martínez Vazquez, Javier Burruchaga, John Bushweller, Caroline A Lamb, Isabel A Lüthy, Claudia Lanari, Cecilia Pérez Piñero.
      Overcoming luminal breast cancer (BrCa) progression remains a critical challenge for improved overall patient survival. RUNX2 has emerged as a protein related to aggressiveness in triple-negative BrCa, however its role in luminal tumors remains elusive. We have previously shown that active FGFR2 (FGFR2-CA) contributes to increased tumor growth and that RUNX2 expression was high in hormone-independent mouse mammary carcinomas. To elucidate the interaction between FGFR2 and RUNX2 in human BrCa, we investigated their roles in tumor progression and treatment responsiveness. Increased FGFR2 activity resulted in higher RUNX2 expression, cell proliferation, and metastasis. In contrast, silencing FGFR2 reduced these parameters. Overexpression of RUNX2 in FGFR2-silenced cells rescued the inhibitory effects, promoting a more aggressive phenotype, even if compared with the wt RUNX2-transfected cells, which also had increased aggressiveness compared with naïve-transfected cells. RUNX2-overexpressing tumors were insensitive to endocrine- or FGFR inhibitor treatments. Notably, the CBFβ-RUNX complex inhibitor, AI-14-91, demonstrated great effectiveness in vitro. In a small cohort of luminal BrCa patients, nuclear RUNX2 expression was associated with tumor recurrence. Transcriptomic analysis strongly supported these data showing that patients with luminal carcinomas with high RUNX2 activity score have a worse progression-free interval than those with low RUNX2 activity. Our findings suggest a complex interplay between FGFR2 and RUNX2 in regulating tumor aggressiveness. This study underscores the significance of RUNX2 in luminal BrCa progression and posits RUNX2 as a promising therapeutic target and as a potential prognostic biomarker in luminal BrCa patients.
    Keywords:  FGFR; RUNX2; breast cancer; endocrine resistance; endocrine therapy
    DOI:  https://doi.org/10.1002/ijc.35302
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