Carbonic anhydrase-9 expression levels and prognosis in human breast cancer: association with treatment outcome

Actinomycin V, an analog of actinomycin D produced by the marine-derived actinomycete Streptomyces sp., possessing a 4-ketoproline instead of a 4-proline in actinomycin D. In this study, the involvement of snail/slug-mediated epithelial-mesenchymal transition (EMT) in the anti-migration and -invasion actions of actinomycin V was investigated in human breast cancer MDA-MB-231 cells in vitro. Cell proliferation effect was evaluated by 3-(4,5-Dimethylthiazol)-2,5-diphenyltetrazolium bromide (MTT) assay. Wound-healing and Transwell assay were performed to investigate the anti-migration and -invasion effects of actinomycin V. Western blotting was used to detect the expression levels of E-cadherin, N-cadherin, vimentin, snail, slug, zinc finger E-box binding homeobox 1 (ZEB1), and twist proteins and the mRNA levels were detected by rt-PCR. Actinomycin V showed stronger cytotoxic activity than that of actinomycin D. Actinomycin V up-regulated both of the protein and mRNA expression levels of E-cadherin and down-regulated that of N-cadherin and vimentin in the same cells. In this connection, actinomycin V decreased the snail and slug protein expression, and consequently inhibited cells EMT procession. Our results suggest that actinomycin V inhibits EMT-mediated migration and invasion via decreasing snail and slug expression, which exhibits therapeutic potential for the treatment of breast cancer and further toxicity investigation in vivo is needed.

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Non-receptor tyrosine kinase 2 reaches its lowest expression levels in human breast cancer during regional nodal metastasis

Clinical & Experimental Metastasis ◽

10.1007/s10585-011-9437-1 ◽

2011 ◽

Vol 29 (2) ◽

pp. 143-153 ◽

Cited By ~ 5

Author(s):

Qing-Xiang Amy Sang ◽

Yan-Gao Man ◽

You Me Sung ◽

Zahraa I. Khamis ◽

Lihua Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Tyrosine Kinase ◽

Receptor Tyrosine Kinase ◽

Human Breast Cancer ◽

Nodal Metastasis ◽

Human Breast ◽

Expression Levels ◽

Tyrosine Kinase 2 ◽

Regional Nodal Metastasis

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BCL-XL blockage in TNBC models confers vulnerability to inhibition of specific cell cycle regulators

10.1101/2021.03.16.435600 ◽

2021 ◽

Author(s):

Olivier Castellanet ◽

Fahmida Ahmad ◽

Yaron Vinik ◽

Gordon B Mills ◽

Bianca H Habermann ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Human Breast Cancer ◽

Specific Cell ◽

Cell Cycle Regulators ◽

Human Breast ◽

Primary Resistance ◽

Western Blots ◽

Expression Levels ◽

Cellular Localisation

Cell cycle regulators are frequently altered in Triple-Negative Breast Cancer (TNBC). Emerging agents targeting these signals offer the possibility to design new combinatorial therapies. However, preclinical models that recapitulate TNBC primary resistance and heterogeneity are essential to evaluate the potency of these combined treatments. Methods: Bioinformatic processing of human breast cancer datasets was used to analyse correlations between expression levels of cell cycle regulators and patient survival outcome. The MMTV-R26Met mouse model of TNBC resistance and heterogeneity was employed to analyse expression and targeting vulnerability of cell cycle regulators in the presence of BCL-XL blockage. Robustness of outcomes and selectivity was further explored using a panel of human breast cancer cells. Alterations of protein expression, phosphorylation, and/or cellular localisation were analysed by western blots, reverse phase protein array, and immunocytochemistry. Bioinformatics was performed to highlight drug's mechanisms of action. Results: We report that high expression levels of BCL-XL and specific cell cycle regulators correlate with poor survival outcomes of TNBC patients. Blockage of BCL-XL confers vulnerability to drugs targeting CDK1/2/4, but not FOXM1, CDK4/6, Aurora A and Aurora B, to all MMTV-R26Met and human TNBC cell lines tested. Mechanistically, we show that, co-targeting of BCL-XL and CDK1/2/4 synergistically inhibited cell growth by combinatorial depletion of survival and RTK/AKT signals, and concomitantly restoring FOXO3a tumour suppression actions. This was accompanied by an accumulation of DNA damage and consequently apoptosis. Conclusions: Our studies illustrate the possibility to exploit the vulnerability of TNBC cells to CDK1/2/4 inhibition by targeting BCL-XL. Moreover, they underline that specificity matters in targeting cell cycle regulators for combinatorial anticancer therapies.

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