scholarly journals Marizomib suppresses triple-negative breast cancer via proteasome and oxidative phosphorylation inhibition

2019 ◽  
Author(s):  
Prahlad V. Raninga ◽  
Andy Lee ◽  
Debottam Sinha ◽  
Lan-feng Dong ◽  
Keshava K. Datta ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Oxidative Phosphorylation ◽  
Brain Metastases ◽  
Triple Negative Breast Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Triple Negative ◽  
Breast Cancer Subtype ◽  
Proteasome Inhibition ◽  
Breast Cancer Patients ◽  
Mesenchymal Transition

AbstractLacking effective targeted therapies, triple-negative breast cancer (TNBCs) is highly aggressive with development of metastasis especially brain, and remains clinically challenging breast cancer subtype to treat. Despite the survival dependency on the proteasome pathway genes, FDA-approved proteasome inhibitors induced minimal clinical response in breast cancer patients due to weak proteasome inhibition. Here, we show that a potent proteasome inhibitor Marizomib (Mzb) inhibits multiple proteasome catalytic activities and induces a better anti-tumor response in TNBC cell lines and patient-derived xenografts alone and in combination with the standard-of-care chemotherapy. Mechanistically, Mzb inhibits oxidative phosphorylation (OXPHOS) via PGC-1α suppression in conjunction with proteasome inhibition in TNBC cells. Mzb reduces lung and brain metastases by reducing the number of circulating tumor cells and the expression of multiple genes involved in the epithelial-to-mesenchymal transition. Furthermore, Mzb-induced OXPHOS inhibition upregulates glycolysis to meet the energetic demands of TNBC cells and, hence, combined inhibition of glycolysis with Mzb exposure leads to a synergistic anti-cancer activity. Collectively, our data provide a strong rationale for a clinical evaluation of Mzb in primary and metastatic TNBC patients.One Sentence SummaryMarizomib inhibits primary tumor growth, and also reduces lung and brain metastases in pre-clinical models of triple-negative breast cancer.

scholarly journals Standard of Care and Promising New Agents for the Treatment of Mesenchymal Triple-Negative Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1080
Author(s):  
Silvia Mezi ◽  
Andrea Botticelli ◽  
Giulia Pomati ◽  
Bruna Cerbelli ◽  
Simone Scagnoli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Triple Negative ◽  
Current Knowledge ◽  
Standard Of Care ◽  
Transition Process ◽  
Breast Cancer Patients ◽  
Mesenchymal Transition ◽  
Expression Of Genes

The pathologic definition of triple negative breast cancer (TNBC) relies on the absence of expression of estrogen, progesterone and HER2 receptors. However, this BC subgroup is distinguished by a wide biological, molecular and clinical heterogeneity. Among the intrinsic TNBC subtypes, the mesenchymal type is defined by the expression of genes involved in the epithelial to mesenchymal transition, stromal interaction and cell motility. Moreover, it shows a high expression of genes involved in proliferation and an immune-suppressive microenvironment. Several molecular alterations along different pathways activated during carcinogenesis and tumor progression have been outlined and could be involved in immune evasion mechanisms. Furthermore, reverting epithelial to mesenchymal transition process could lead to the overcoming of immune-resistance. This paper reviews the current knowledge regarding the mesenchymal TNBC subtype and its response to conventional therapeutic strategies, as well as to some promising molecular target agents and immunotherapy. The final goal is a tailored combination of cytotoxic drugs, target agents and immunotherapy in order to restore immunocompetence in mesenchymal breast cancer patients.

scholarly journals Combined Phosphoproteomics and Bioinformatics Strategy in Deciphering Drug Resistant Related Pathways in Triple Negative Breast Cancer

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Xinyu Deng ◽  
Morris Kohanfars ◽  
Huan Ming Hsu ◽  
Puneet Souda ◽  
Joe Capri ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Triple Negative ◽  
Drug Resistant ◽  
Breast Cancer Patients ◽  
Mesenchymal Transition ◽  
Chemotherapy Drugs ◽  
Tnbc Cell

Because of the absence of a clear therapeutic target for triple negative breast cancer (TNBC), conventional chemotherapy is the only available systemic treatment option for these patients. Despite chemotherapy treatment, TNBC patients still have worse prognosis when compared with other breast cancer patients. The study is to investigate unique phosphorylated proteins expressed in chemoresistant TNBC cell lines. In the current study, twelve TNBC cell lines were subjected to drug sensitivity assays against chemotherapy drugs docetaxel, doxorubicin, gemcitabine, and cisplatin. Based on their half maximal inhibitory concentrations, four resistant and two sensitive cell lines were selected for further analysis. The phosphopeptides from these cells were enriched with TiO2 beads and fractionated using strong cation exchange. 1,645 phosphoprotein groups and 9,585 unique phosphopeptides were identified by a high throughput LC-MS/MS system LTQ-Orbitrap. The phosphopeptides were further filtered with Ascore system and 1,340 phosphoprotein groups, 2,760 unique phosphopeptides, and 4,549 unique phosphosites were identified. Our study suggested that differentially phosphorylated Cdk5, PML, AP-1, and HSF-1 might work together to promote vimentin induced epithelial to mesenchymal transition (EMT) in the drug resistant cells. EGFR and HGF were also shown to be involved in this process.

MALT1 is a Targetable Driver of Epithelial-to-Mesenchymal Transition in Claudin-low, Triple-Negative Breast Cancer

2021 ◽  
pp. molcanres.0208.2021
Author(s):  
Jia-Ying (Lloyd) Lee ◽  
Prasanna Ekambaram ◽  
Neil M. Carleton ◽  
Dong Hu ◽  
Linda R. Klei ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Triple Negative ◽  
Mesenchymal Transition

The role of systemic treatment after whole brain radiotherapy (WBRT) in breast cancer patients with brain metastases: Differences depending on biological subtype

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1027-1027
Author(s):  
A. Niwinska ◽  
M. Murawska ◽  
I. Lemanska ◽  
J. Milewska
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Median Survival ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Systemic Treatment ◽  
Performance Status ◽  
Poor Performance Status ◽  
Breast Cancer Patients ◽  
Her 2

1027 Background: The aim of the study was to analyze the efficacy of systemic treatment (chemotherapy [chth], endocrine therapy, targeted therapy) performed after WBRT in patients (pts) with breast cancer and brain metastases. Methods: The group of 222 consecutive breast cancer pts with brain metastases treated in one institution in the years 2003–2006 was divided into four biological subgroups based on ER, PR, and HER-2 receptors’ expression: HER-2(+++)ER/PR(-); HER-2(+++)ER/PR(+); ER(-)PR(-)HER-2(-); and ER/PR(+)HER-2(-). WBRT was performed in 219 (99%) pts. Systemic therapy after WBRT was continued in 160 (72%) pts. Clinically, patients with triple-negative breast cancer were more often in poor performance status (KPS<60%) than the others (51% vs. 28%, respectively). Survivals from brain metastases without and with systemic treatment were compared in four mentioned biological subgroups. Results: Median survival from brain metastases in the entire group was 7.5 months. In the group of ER/PR(+)HER-2(-) median survival without and with systemic therapy was 3 and 14 months, respectively (p = 0.007). In the group of HER-2(+++)ER/PR(+) median survival without further treatment, after chth and after chth with trastuzumab was 2, 8, and 13 months, respectively (p = 0.000) and in the group of HER-2(+++)ER/PR(-) median survival without further treatment, after chth and after chth with trastuzumab was 4, 8, and 10 months, respectively (p = 0.004). In triple-negative breast cancer patients median survival without and with chemotherapy was 3 and 4 months, respectively (p = 0.75). Conclusions: Systemic treatment (chth, endocrine therapy, targeted therapy) continued after WBRT in breast cancer pts with brain metastases prolongs survival in three of four biological subgroups. In the group of HER-2-positive breast cancer pts, trastuzumab added to chth had independent positive impact on survival. No benefit was observed in the subgroup of triple-negative breast cancer pts; it would be the result of refractory disease and the fact, that more pts were in poor performance status. No significant financial relationships to disclose.

Sign in / Sign up

Export Citation Format

Share Document