Molecular Targets and Promising Therapeutics of Triple-Negative Breast Cancer

Ryu, Won-Ji; Sohn, Joohyuk

doi:10.3390/ph14101008

Cited by 12 publications

(9 citation statements)

References 101 publications

(131 reference statements)

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“…Researchers from the field have investigated the inhibition of PI3K , which causes DNA damage, downregulates BRCA 1 and 2 , increases poly-ADP ribosylation and, finally, activates PARP inhibition. PI3K and PARP inhibitors have been investigated in a mouse model for BRCA1 -related tumors, and provide synergistic effects in their treatment [ 42 ]. In addition, PI3K -mTOR is inhibited by GDC-0980, and was tested in combination with veliparib and carboplatin in a TNBC model.…”

Section: Mechanism Of Poly (Adp-ribose) Polymerase Inhibitionmentioning

confidence: 99%

“…Furthermore, a combination of veliparib and carboplatin has been shown to be effective against xenograft tumors [ 40 ]. The mTOR signaling pathway is an important target strategy for TNBC [ 42 ]—it causes downregulation of the PI3K pathway and also suppresses the regulation of TNBC cell lines [ 3 , 42 ]. A combination of PARP inhibitors and mTOR inhibitors has shown significant activity in TNBC cell lines [ 43 , 44 ].…”

Section: Mechanism Of Poly (Adp-ribose) Polymerase Inhibitionmentioning

confidence: 99%

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Role of PARP in TNBC: Mechanism of Inhibition, Clinical Applications, and Resistance

2021

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Triple-negative breast cancer is a combative cancer type with a highly inflated histological grade that leads to poor theragnostic value. Gene, protein, and receptor-specific targets have shown effective clinical outcomes in patients with TNBC. Cells are frequently exposed to DNA-damaging agents. DNA damage is repaired by multiple pathways; accumulations of mutations occur due to damage to one or more pathways and lead to alterations in normal cellular mechanisms, which lead to development of tumors. Advances in target-specific cancer therapies have shown significant momentum; most treatment options cause off-target toxicity and side effects on healthy tissues. PARP (poly(ADP-ribose) polymerase) is a major protein and is involved in DNA repair pathways, base excision repair (BER) mechanisms, homologous recombination (HR), and nonhomologous end-joining (NEJ) deficiency-based repair mechanisms. DNA damage repair deficits cause an increased risk of tumor formation. Inhibitors of PARP favorably kill cancer cells in BRCA-mutations. For a few years, PARPi has shown promising activity as a chemotherapeutic agent in BRCA1- or BRCA2-associated breast cancers, and in combination with chemotherapy in triple-negative breast cancer. This review covers the current results of clinical trials testing and future directions for the field of PARP inhibitor development.

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Section: Mechanism Of Poly (Adp-ribose) Polymerase Inhibitionmentioning

confidence: 99%

Section: Mechanism Of Poly (Adp-ribose) Polymerase Inhibitionmentioning

confidence: 99%

Role of PARP in TNBC: Mechanism of Inhibition, Clinical Applications, and Resistance

2021

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“…Molecular altercations of the BL1 subtype include MYC and RB1 amplifications and more commonly result in invasive ductal carcinoma. Genes altered in the BL2 subtype are associated with growth factor signaling, such as epidermal growth factor, Wnt/βcatenin, and mTOR pathways [8]. The IM subtype mainly proliferates via immune cell and cytokine signaling, and is characterized by alterations in Th1 and Th2 immune responses, as well as natural killer cells.…”

Section: Introductionmentioning

confidence: 99%

“…MSL gene subtypes also function via cell signaling and growth components. Both M and MSL subtypes produce histologically similar sarcoma-like and squamous epithelial cell-like tumors [8]. Finally, the LAR subtype is rather unique in that it is characterized by genes heavily involved in hormone regulation such as steroid synthesis, notably that of androgens and estrogens [6].…”

Section: Introductionmentioning

confidence: 99%

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Molecular Targets of Triple-Negative Breast Cancer: Where Do We Stand?

Newton

Mueller

Treadwell

et al. 2022

Cancers

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Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer. Due to its heterogeneity and lack of hormone receptor expression, this subtype is more likely to metastasize and resist treatment attempts than are other forms of breast cancer. Due to the absence of targetable receptors, chemotherapy and breast conserving surgery have been the predominant treatment options for patients. However, resistance to chemotherapy and local recurrence of the tumors is frequent. Emerging immunotherapies have begun to change treatment plans for patients diagnosed with TNBC. In this review, we discuss the various immune pathways identified in TNBC and the role they play as targets for new potential treatment choices. Various therapeutic options that inhibit key pathways in cellular growth cycles, DNA repair mechanisms, epithelial mesenchymal transition, and immunosuppression have been shown to improve survival in patients with this disease. With promising results thus far, continued studies of immunotherapy and neoadjuvant therapy options for TNBC are likely to alter the treatment course for these diagnoses in the future.

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Functionalized siRNA-chitosan nanoformulations promote triple-negative breast cancer cell death via blocking the miRNA-21/AKT/ERK signaling axis: in-silico and in vitro studies

Abdulmalek,

Saleh,

Shahin

et al. 2024

Naunyn-Schmiedeberg's Arch Pharmacol

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Oncogenic microRNA (miRNA), especially miRNA-21 upregulation in triple-negative breast cancer (TNBC), suggests a new class of therapeutic targets. In this study, we aimed to create GE11 peptide-conjugated small interfering RNA-loaded chitosan nanoparticles (GE11-siRNA-CSNPs) for the targeting of EGFR overexpressed TNBC and selectively inhibit miRNA-21 expression. A variety of in-silico and in vitro cellular and molecular studies were conducted to investigate the binding affinities of specific targets used as well as the anticancer efficacies and mechanisms of GE11-siRNA-CSNPs in TNBC cells. An in-silico assessment reveals a distinct binding affinity of miRNA-21 with siRNA as well as between the extracellular domain of EGFR and synthesized peptides. Notably, the in vitro results showed that GE11-siRNA-CSNPs were revealed to have better cytotoxicity against TNBC cells. It significantly inhibits miRNA-21 expression, cell migration, and colony formation. The results also indicated that GE11-siRNA-CSNPs impeded cell cycle progression. It induces cell death by reducing the expression of the antiapoptotic gene Bcl-2 and increasing the expression of the proapoptotic genes Bax, Caspase 3, and Caspase 9. Additionally, the docking analysis and immunoblot investigations verified that GE1-siRNA-CSNPs, which specifically target TNBC cells and suppress miRNA-21, can prevent the effects of miRNA-21 on the proliferation of TNBC cells via controlling EGFR and subsequently inhibiting the PI3K/AKT and ERK1/2 signaling axis. The GE11-siRNA-CSNPs design, which specifically targets TNBC cells, offers a novel approach for the treatment of breast cancer with improved effectiveness. This study suggests that GE11-siRNA-CSNPs could be a promising candidate for further assessment as an additional strategy in the treatment of TNBC. Graphical Abstract

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Molecular Targets and Promising Therapeutics of Triple-Negative Breast Cancer

Cited by 12 publications

References 101 publications

Role of PARP in TNBC: Mechanism of Inhibition, Clinical Applications, and Resistance

Role of PARP in TNBC: Mechanism of Inhibition, Clinical Applications, and Resistance

Molecular Targets of Triple-Negative Breast Cancer: Where Do We Stand?

Functionalized siRNA-chitosan nanoformulations promote triple-negative breast cancer cell death via blocking the miRNA-21/AKT/ERK signaling axis: in-silico and in vitro studies

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