3 research outputs found
TGFβ Governs the Pleiotropic Activity of NDRG1 in Triple-Negative Breast Cancer Progression
In triple-negative breast cancer (TNBC), the pleiotropic NDRG1 (N-Myc downstream regulated gene 1)
promotes progression and worse survival, yet contradictory results were documented, and the mechanisms
remain unknown. Phosphorylation and localization could drive NDRG1 pleiotropy, nonetheless, their role in
TNBC progression and clinical outcome was not investigated. We found enhanced p-NDRG1 (Thr346) by
TGFβ1 and explored whether it drives NDRG1 pleiotropy and TNBC progression. In tissue microarrays of 81
TNBC patients, we identified that staining and localization of NDRG1 and p-NDRG1 (Thr346) are biomarkers
and risk factors associated with shorter overall survival. We found that TGFβ1 leads NDRG1, downstream of
GSK3β, and upstream of NF-κB, to differentially regulate migration, invasion, epithelial-mesenchymal transition,
tumor initiation, and maintenance of different populations of cancer stem cells (CSCs), depending on the
progression stage of tumor cells, and the combination of TGFβ and GSK3β inhibitors impaired CSCs. The
present study revealed the striking importance to assess both total NDRG1 and p-NDRG1 (Thr346)
positiveness and subcellular localization to evaluate patient prognosis and their stratification. NDRG1
pleiotropy is driven by TGFβ to differentially promote metastasis and/or maintenance of CSCs at different
stages of tumor progression, which could be abrogated by the inhibition of TGFβ and GSK3β.Instituto de Salud Carlos III
European Commission PI15/00336
PI19/01533
CP14/00197
CP19/00029
PIE16/00045Ministry of Science and Innovation, Spain (MICINN)Instituto de Salud Carlos IIISpanish Government RTI2018.101309B-C22Chair "Doctors Galera-Requena in cancer stem cell research" CMC-CTS963European Regional Development Fund (European Union)Ministerio de Universidades FPU19/04450Junta de Andalucia RH-0139-2020Sistema Nacional de Garantia Juvenil (Fondo Social Europeo) 8064Junta de Andalucia, Consejeria de Transformacion Economica, Industria, Conocimiento y Universidades DOC_01686Fundacion Cientifica Asociacion Espanola Contra el Cancer, Junta Provincial de Jaen (AECC) PRDJA19001BLA
Drug Repurposing for Triple-Negative Breast Cancer
Instituto de Salud Carlos III
CP19/00029
CP14/00197
PI19/01533
PI15/00336Spanish Government
RTC-2016-5674-1European Union (EU)Ministerio de Ciencia, Innovación y Universidades
FPU19/04450Fundación Científica Asociación Española Contra el Cáncer, Junta Provincial de Jaén (AECC)
PRDJA19001BLA
Unlocking the effective alliance of β-lapachone and hydroxytyrosol against triple-negative breast cancer cells
Triple-negative breast cancer (TNBC) is characterised by its aggressiveness and resistance to chemotherapy, demanding the development of effective strategies against its unique characteristics. Derived from lapacho tree bark, β-lapachone (β-LP) selectively targets cancer cells with elevated levels of the detoxifying enzyme NQO1. Hydroxytyrosol (HT) is a phenolic compound derived from olive trees with important anticancer properties that include the inhibition of cancer stem cells (CSCs) and metastatic features in TNBC, as well as relevant antioxidant activities by mechanisms such as the induction of NQO1. We aimed to study whether these compounds could have synergistic anticancer activity in TNBC cells and the possible role of NQO1. For this pourpose, we assessed the impact of β-LP (0.5 or 1.5 μM) and HT (50 and 100 μM) on five TNBC cell lines. We demonstrated that the combination of β-LP and HT exhibits anti-proliferative, pro-apoptotic, and cell cycle arrest effects in several TNBC cells, including docetaxel-resistant TNBC cells. Additionally, it effectively inhibits the self-renewal and clonogenicity of CSCs, modifying their aggressive phenotype. However, the notable impact of the β-LP-HT combination does not appear to be solely associated with the levels of the NQO1 protein and ROS. RNA-Seq analysis revealed that the combination's anticancer activity is linked to a strong induction of endoplasmic reticulum stress and apoptosis through the unfolded protein response. In conclusion, in this study, we demonstrated how the combination of β-LP and HT could offer an affordable, safe, and effective approach against TNBC.</p