Cooperation between monocytes and breast cancer cells promotes factors involved in cancer aggressiveness

158 Background: αvβ3 integrin-overexpression in tumor associated vasculature is a marker of poor prognosis in breast cancer. A positive correlation between αvβ3 integrin and overexpression of Interleukin-8 (IL-8), a multifunctional cytokine associated with breast cancer aggressiveness was recently demonstrated. Here, we addressed the effects of IL-8 in migration and integrin expression in breast cancer cells. Methods: The IL-8 overexpressing breast cancer cells MDA-MB-231 and HS 578t were treated with IL-8 siRNA and evaluated for cells motility and alterations in the expression of αvβ3. Western Blotting to identify the status of PI3K, Akt and NF-κB. Results: In this study, we found that αvβ3 expression was decreased by IL-8 siRNA, especially the expression of β3. Treatment with αvβ3-blocking antibody LM609 and β3 siRNA significantly reduced invasion in the IL-8 overexpressing cells MDA-MB-231 and HS 578t. The phosphorylation of PI3K, Akt and NF-κB was abrogated after IL-8 siRNA treatment. The IL-8 siRNA can also decrease the binding of β3 promoter and the NF-κB-P65. Conclusions: These results indicate that IL-8 enhances the motility of highly invasive breast cancer cells by regulating αvβ3 expression partially through PI3K/Akt/ NF-κB signal transduction pathway.

Download Full-text

Omega 3-DHA and Delta-Tocotrienol Modulate Lipid Droplet Biogenesis and Lipophagy in Breast Cancer Cells: the Impact in Cancer Aggressiveness

Nutrients ◽

10.3390/nu11061199 ◽

2019 ◽

Vol 11 (6) ◽

pp. 1199 ◽

Cited By ~ 1

Author(s):

Pizato ◽

Kiffer ◽

Luzete ◽

Assumpção ◽

Correa ◽

...

Keyword(s):

Breast Cancer ◽

Vitamin E ◽

Cancer Cells ◽

Lipid Droplet ◽

Breast Cancer Cells ◽

Positive Impact ◽

Bioactive Molecules ◽

Omega 3 ◽

Cancer Aggressiveness ◽

The Impact

Omega 3-docosahexaenoic acid (DHA) and vitamin E Delta-tocotrienol (Delta-T3) are extensively studied as protective nutrients against cancer development. Little is known about the biological mechanisms targeted by these bioactive molecules on lipid droplet (LD) biogenesis, an important breast cancer aggressiveness marker, and the occurrence of lipophagy in breast cancer cells. The aim of this study was to investigate the effect of DHA, Delta-T3 and DHA plus Delta-T3 co-treatment in LD biogenesis and lipophagy process in triple negative breast cancer cell line MDA-MB-231. Cells were treated with 50 μM DHA and/or 5 μM Delta-T3. Our results demonstrated that DHA can trigger an increase in LD biogenesis and co-treatment with Delta-T3 was able to reduce this LD biogenesis. In addition, we showed that a higher cytoplasmic LD content is associated with a higher breast cancer cells malignance and proliferation. Reduction of cytoplasmic LD content by silencing ADRP (adipose differentiation-related protein), a structural LD protein, also decreased cell proliferation in MDA-MB-231 cells. Treatment with DHA and Delta-T3 alone or co-treatment did not reduce cell viability. Moreover, we showed here that DHA can trigger lipophagy in MDA-MB-231 cells and DHA plus Delta-T3 co-treatment was able to enhance this lipophagy process. Our findings demonstrated that co-treatment with DHA plus Delta-T3 in MDA-MB-231 cells could reduce LD biogenesis and potentiate lipophagy in these cells, possibly having a positive impact to inhibit breast cancer malignancy. Therefore, suitable doses of DHA and Delta-T3 vitamin E isoform supplementation can be a prominent tool in therapeutic treatments against breast cancer.

Download Full-text

Local variations of HER2 dimerization in breast cancer cells discovered by correlative fluorescence and liquid electron microscopy

Science Advances ◽

10.1126/sciadv.1500165 ◽

2015 ◽

Vol 1 (6) ◽

pp. e1500165 ◽

Cited By ~ 55

Author(s):

Diana B. Peckys ◽

Ulrike Korf ◽

Niels de Jonge

Keyword(s):

Breast Cancer ◽

Electron Microscopy ◽

Fluorescence Microscopy ◽

Cancer Cells ◽

Single Molecule ◽

Breast Cancer Cells ◽

Pair Correlation ◽

Resting Cells ◽

Membrane Topography ◽

Cancer Aggressiveness

The formation of HER2 homodimers plays an important role in breast cancer aggressiveness and progression; however, little is known about its localization. We have studied the intra- and intercellular variation of HER2 at the single-molecule level in intact SKBR3 breast cancer cells. Whole cells were visualized in hydrated state with correlative fluorescence microscopy and environmental scanning electron microscopy (ESEM). The locations of individual HER2 receptors were detected using an anti-HER2 affibody in combination with a quantum dot (QD), a fluorescent nanoparticle. Fluorescence microscopy revealed considerable differences of HER2 membrane expression between individual cells and between different membrane regions of the same cell (that is, membrane ruffles and flat areas). Subsequent ESEM of the corresponding cellular regions provided images of individually labeled HER2 receptors. The high spatial resolution of 3 nm and the close proximity between the QD and the receptor allowed quantifying the stoichiometry of HER2 complexes, distinguishing between monomers, dimers, and higher-order clusters. Downstream data analysis based on calculating the pair correlation function from receptor positions showed that cellular regions exhibiting membrane ruffles contained a substantial fraction of HER2 in homodimeric state. Larger-order clusters were also present. Membrane areas with homogeneous membrane topography, on the contrary, displayed HER2 in random distribution. Second, HER2 homodimers appeared to be absent from a small subpopulation of cells exhibiting a flat membrane topography, possibly resting cells. Local differences in homodimer presence may point toward functional differences with possible relevance for studying metastasis and drug response.

Download Full-text

G9a Knockdown Suppresses Cancer Aggressiveness by Facilitating Smad Protein Phosphorylation through Increasing BMP5 Expression in Luminal A Type Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms23020589 ◽

2022 ◽

Vol 23 (2) ◽

pp. 589

Author(s):

Yunho Jin ◽

Shinji Park ◽

Soon-Yong Park ◽

Chae-Young Lee ◽

Da-Young Eum ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Progression ◽

Protein Phosphorylation ◽

Cancer Cells ◽

Intracellular Signaling ◽

Breast Cancer Cells ◽

Migration And Invasion ◽

Antitumor Effects ◽

Cancer Aggressiveness ◽

Smad Protein

Epigenetic abnormalities affect tumor progression, as well as gene expression and function. Among the diverse epigenetic modulators, the histone methyltransferase G9a has been focused on due to its role in accelerating tumorigenesis and metastasis. Although epigenetic dysregulation is closely related to tumor progression, reports regarding the relationship between G9a and its possible downstream factors regulating breast tumor growth are scarce. Therefore, we aimed to verify the role of G9a and its presumable downstream regulators during malignant progression of breast cancer. G9a-depleted MCF7 and T47D breast cancer cells exhibited suppressed motility, including migration and invasion, and an improved response to ionizing radiation. To identify the possible key factors underlying these effects, microarray analysis was performed, and a TGF-β superfamily member, BMP5, was selected as a prominent target gene. It was found that BMP5 expression was markedly increased by G9a knockdown. Moreover, reduction in the migration/invasion ability of MCF7 and T47D breast cancer cells was induced by BMP5. Interestingly, a G9a-depletion-mediated increase in BMP5 expression induced the phosphorylation of Smad proteins, which are the intracellular signaling mediators of BMP5. Accordingly, we concluded that the observed antitumor effects may be based on the G9a-depletion-mediated increase in BMP5 expression and the consequent facilitation of Smad protein phosphorylation.

Download Full-text

Connexin-46 Contained in Extracellular Vesicles Enhance Malignancy Features in Breast Cancer Cells

Biomolecules ◽

10.3390/biom10050676 ◽

2020 ◽

Vol 10 (5) ◽

pp. 676 ◽

Cited By ~ 3

Author(s):

Rodrigo A. Acuña ◽

Manuel Varas-Godoy ◽

Viviana M. Berthoud ◽

Ivan E. Alfaro ◽

Mauricio A. Retamal

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Extracellular Vesicles ◽

Intercellular Communication ◽

Breast Cancer Cells ◽

Recipient Cell ◽

Cell Types ◽

Migration And Invasion ◽

Long Distance ◽

Cancer Aggressiveness

Under normal conditions, almost all cell types communicate with their neighboring cells through gap junction channels (GJC), facilitating cellular and tissue homeostasis. A GJC is formed by the interaction of two hemichannels; each one of these hemichannels in turn is formed by six subunits of transmembrane proteins called connexins (Cx). For many years, it was believed that the loss of GJC-mediated intercellular communication was a hallmark in cancer development. However, nowadays this paradigm is changing. The connexin 46 (Cx46), which is almost exclusively expressed in the eye lens, is upregulated in human breast cancer, and is correlated with tumor growth in a Xenograft mouse model. On the other hand, extracellular vesicles (EVs) have an important role in long-distance communication under physiological conditions. In the last decade, EVs also have been recognized as key players in cancer aggressiveness. The aim of this work was to explore the involvement of Cx46 in EV-mediated intercellular communication. Here, we demonstrated for the first time, that Cx46 is contained in EVs released from breast cancer cells overexpressing Cx46 (EVs-Cx46). This EV-Cx46 facilitates the interaction between EVs and the recipient cell resulting in an increase in their migration and invasion properties. Our results suggest that EV-Cx46 could be a marker of cancer malignancy and open the possibility to consider Cx46 as a new therapeutic target in cancer treatment.

Download Full-text