The role of NF-κB in breast cancer initiation, growth, metastasis, and resistance to chemotherapy

Pavitra, E.; Kancharla, Jyothsna; Gupta, Vivek Kumar; Prasad, Konasale M.; Sung, Ju Yong; Kim, Jigyeong; Tej, Mandava Bhuvan; Choi, Rino; Lee, Jeong‐Hwan; Han, Young‐Kyu; Raju, G. Seeta Rama; Lakkakula, Bhaskar Vks; Huh, Yun Suk

doi:10.1016/j.biopha.2023.114822

Cited by 37 publications

(15 citation statements)

References 206 publications

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“…Moreover, the activation of NF-kB was also closely associated with the metastatic progression in several types of cancer [43][44][45][46][47][48]. In breast cancer, NF-kB played a pivotal role in triggering cancer initiation, growth, metastasis and resistance to chemotherapy [49]. Here we further show that NF-kB is sequentially activated by GRK6, b-Arrestin 2 and MAPKs and mediates the expression of EMT-related genes and metastatic progression in TNBC cells.…”

Section: Discussionmentioning

confidence: 99%

GRK6 palmitoylation dictates triple-negative breast cancer metastasis via recruiting the β-Arrestin 2/MAPKs/NF-κB signaling axis

Wang,

Lin,

Lin

et al. 2024

Preprint

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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 vitrocellular 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 b-Arrestin 2/mitogen-activated protein kinases (MAPKs)/NF-kB signaling axis and fostering the metastatic potentials of TNBC cells. Accordingly, the pharmaceutical inhibition of GRK6 kinase activity dramatically suppressed the activation of b-Arrestin 2, MAPKs and NF-kB and the cellular migration ability of highly metastatic MDA-MB231 cells. Sequentially blocking the b-Arrestin 2/MAPKs/NF-kB 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.

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Section: Discussionmentioning

confidence: 99%

GRK6 palmitoylation dictates triple-negative breast cancer metastasis via recruiting the β-Arrestin 2/MAPKs/NF-κB signaling axis

Wang,

Lin,

Lin

et al. 2024

Preprint

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“…260 YM155, a survivin inhibitor, can potentiate TRAIL-mediated apoptosis through inhibiting Mcl-1, c-FLIP, and NF-κB in breast cancer. 261 Additionally, NF-κB can transcriptionally activate the Bcl-2 family, which inhibits BAX/BAK and thus prevents cytochrome C release and apoptosome formation. Furthermore, NF-κB modulates p53-mediated apoptosis via promoting the polyubiquitylation and degradation of p53.…”

Section: Nf-κb Signaling In Human Diseasesmentioning

confidence: 99%

NF-κB in biology and targeted therapy: new insights and translational implications

Guo,

Jin,

Chen

et al. 2024

Sig Transduct Target Ther

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NF-κB signaling has been discovered for nearly 40 years. Initially, NF-κB signaling was identified as a pivotal pathway in mediating inflammatory responses. However, with extensive and in-depth investigations, researchers have discovered that its role can be expanded to a variety of signaling mechanisms, biological processes, human diseases, and treatment options. In this review, we first scrutinize the research process of NF-κB signaling, and summarize the composition, activation, and regulatory mechanism of NF-κB signaling. We investigate the interaction of NF-κB signaling with other important pathways, including PI3K/AKT, MAPK, JAK-STAT, TGF-β, Wnt, Notch, Hedgehog, and TLR signaling. The physiological and pathological states of NF-κB signaling, as well as its intricate involvement in inflammation, immune regulation, and tumor microenvironment, are also explicated. Additionally, we illustrate how NF-κB signaling is involved in a variety of human diseases, including cancers, inflammatory and autoimmune diseases, cardiovascular diseases, metabolic diseases, neurological diseases, and COVID-19. Further, we discuss the therapeutic approaches targeting NF-κB signaling, including IKK inhibitors, monoclonal antibodies, proteasome inhibitors, nuclear translocation inhibitors, DNA binding inhibitors, TKIs, non-coding RNAs, immunotherapy, and CAR-T. Finally, we provide an outlook for research in the field of NF-κB signaling. We hope to present a stereoscopic, comprehensive NF-κB signaling that will inform future research and clinical practice.

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“…The interplay between Notch, Akt, and p53 in anti-apoptotic signaling highlights the complexity of cell survival regulation in breast cancer. Targeting the Notch pathway in combination with inhibitors of Akt or NF-κB has shown promising results in suppressing TNBC growth in preclinical models, suggesting potential therapeutic strategies for this aggressive breast cancer subtype 123 . Understanding the mechanisms of Notchinduced anti-apoptotic signaling in breast cancer can provide valuable insights for the creation of specific therapies aimed at enhancing the efficacy of apoptosis-inducing treatments and improving outcomes for breast cancer patients 124 .…”

Section: Cell Survivalmentioning

confidence: 99%

Navigating breast cancer complexity: Deciphering the cross talk of Wnt/β catenin and Notch pathways in development and diseases

Rasool,

Bhat,

Khurshid

et al. 2024

Preprint

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This study investigates miRNA impact on lung, colorectal, and epithelial cancers, emphasizing Wnt3’s role in breast tumor growth through WNT signaling and its influence on mammary stem cells. WNT pathway inactivation induces drug-insensitive, quiescent states in breast cancer stem cells, resulting in resistance to multiple drugs. Tamoxifen-resistant breast carcinoma cells activate both canonical and noncanonical WNT signaling, with Wnt3a enhancing tamoxifen resistance in ER+ carcinoma cells. The study also explores breast cancer immunotherapy, highlighting immune checkpoint blockade targeting PD-1/PD-L1 and CTLA-4 as promising avenues. Additionally, the study explores the NOTCH signaling pathways impact on cancer proliferation, apoptosis, invasion and metastasis. Elevated NOTCH receptor and ligand expression particularly in aggressive triple negative breast cancer correlate with poorer treatment outcome, serving as a predictor for adverse results in breast tumors. The review discusses the relevance of Notch signaling in therapy resistance and breast cancer recurrence. The article encapsulates therapeutic advancements targeting the Notch signaling pathway, weighing merits and demerits in the context of breast cancer treatment. Our study provides a comprehensive understanding of the complex interactions within the WNT and Notch signaling pathways in breast cancer, shedding light on potential therapeutic targets and strategies for personalized treatment. This research significantly contributes to the current body of knowledge, offering promise for improved outcomes in breast cancer patients. The findings underscore the importance of WNT and Notch signaling modulation in developing effective therapeutic interventions for breast cancer.

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The role of NF-κB in breast cancer initiation, growth, metastasis, and resistance to chemotherapy

Cited by 37 publications

References 206 publications

GRK6 palmitoylation dictates triple-negative breast cancer metastasis via recruiting the β-Arrestin 2/MAPKs/NF-κB signaling axis

GRK6 palmitoylation dictates triple-negative breast cancer metastasis via recruiting the β-Arrestin 2/MAPKs/NF-κB signaling axis

NF-κB in biology and targeted therapy: new insights and translational implications

Navigating breast cancer complexity: Deciphering the cross talk of Wnt/β catenin and Notch pathways in development and diseases

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