Estrogen-related receptor alpha (ERRα) promotes the migration, invasion and angiogenesis of breast cancer stem cell-like cells.

Breast cancer progression, metastasis and recurrence are largely driven by breast cancer stem cells (BCSCs), which constitute a subset of tumor cells exhibiting stem cell characteristics. In this study, we evaluated the role of estrogen-related receptor alpha (ERRα) in the migration, invasion and angiogenesis of BCSCs. The inhibition of ERRα using XCT790 or knockdown of ERRα using shRNA inhibited the mammosphere formation efficiency, as well as the migration and invasion of BCSCs derived from the mammospheres of MCF7 and MDA-MB-231 (MB231) cells. Conversely, the overexpression of ERRα significantly increased the migration and invasion of BCSCs derived from the mammosphere. In addition, the XCT790 treatment or shERRα significantly downregulated the epithelial-mesenchymal transition (EMT), as evidenced by the downregulation in the expression of vimentin, Snail, Slug and N-cadherin in the mammospheres of MCF7 and MB231 cells. The chorioallantoic membrane assay showed that the conditioned media from XCT790-treated and shERRα cells significantly inhibited blood vessel formation and vessel length. Furthermore, XCT790 treatment or shERRα also downregulated the expression of molecular markers of angiogenesis, such as VEGF-A and Ang-2 in the mammospheres. Conversely, the overexpression of ERRα in MCF7 cells significantly increased both EMT and angiogenesis. These findings suggest that ERRα inhibits the migration, invasion and angiogenesis of BCSCs, suggesting as a potential target for breast cancer therapy.

Estrogen-Related Receptor Alpha (ERRα) Promotes Cancer Stem Cell-Like Characteristics in Breast Cancer.

Cancer stem cells drive tumor initiation, invasion, metastasis and recurrence. In the present study, we have evaluated the role of ERRα in the maintenance of breast cancer stem cells (BCSCs) using breast cancer cell lines. The inhibition of ERRα with the inverse agonist, XCT-790, or the knockdown of ERRα in breast cancer cells significantly reduced the mammosphere formation efficiency and mammosphere size along with a significant reduction in the CD44+/CD24- BCSCs. Treatment with XCT-790 significantly downregulated expression of the transcription factors involved in stem cell maintenance such as Oct4, Klf4, Sox2, Nanog and c-Myc in the mammosphere forming stem cells of MCF7 and MDA-MB-231. In addition, XCT-790 induced cell cycle arrest and apoptosis in the mammosphere-forming cells. The knockdown or inhibition of ERRα downregulated the expression of Notch1 and ß-catenin, whereas the overexpression of ERRα in MCF7 cells upregulated the expression of these proteins. Moreover, the inhibition of ERRα synergistically enhanced the efficacy of paclitaxel in inhibiting the BCSCs. These results show that ERRα is crucial for the maintenance of BCSCs and suggest that ERRα could be a potential target for breast cancer treatment.

Unravelling the Evolutionary Dynamics of High-Risk Klebsiella pneumoniae ST147 Clones: Insights from Comparative Pangenome Analysis.

BACKGROUND: The high prevalence and rapid emergence of antibiotic resistance in high-risk Klebsiella pneumoniae (KP) ST147 clones is a global health concern and warrants molecular surveillance. METHODS: A pangenome analysis was performed using publicly available ST147 complete genomes. The characteristics and evolutionary relationships among ST147 members were investigated through a Bayesian phylogenetic analysis. RESULTS: The large number of accessory genes in the pangenome indicates genome plasticity and openness. Seventy-two antibiotic resistance genes were found to be linked with antibiotic inactivation, efflux, and target alteration. The exclusive detection of the blaOXA-232 gene within the ColKp3 plasmid of KP_SDL79 suggests its acquisition through horizontal gene transfer. The association of seventy-six virulence genes with the acrAB efflux pump, T6SS system and type I secretion system describes its pathogenicity. The presence of Tn6170, a putative Tn7-like transposon in KP_SDL79 with an insertion at the flanking region of the tnsB gene, establishes its transmission ability. The Bayesian phylogenetic analysis estimates ST147's initial divergence in 1951 and the most recent common ancestor for the entire KP population in 1621. CONCLUSIONS: Present study highlights the genetic diversity and evolutionary dynamics of high-risk clones of K. pneumoniae. Further inter-clonal diversity studies will help us understand its outbreak more precisely and pave the way for therapeutic interventions.

α-Lipoic acid prevents the ionizing radiation-induced epithelial-mesenchymal transition and enhances the radiosensitivity in breast cancer cells.

Radiotherapy is routinely used in the treatment of breast cancer. However, its efficiency is often limited by the development of radioresistance and metastasis. The cancer cells surviving irradiation show epithelial-mesenchymal transition (EMT) along with increased migration, invasion and metastasis. In this study, we have evaluated the role of α-lipoic acid in preventing the radiation-induced EMT and in sensitizing the breast cancer cells to radiation. The breast cancer cell lines, MCF-7 and MDA-MB-231 were pretreated with lipoic acid, irradiated and the changes associated with cell growth, clonogenicity, migration, matrix metalloproteinases (MMPs), EMT and TGFß signaling were measured. Our data showed that lipoic acid pretreatment sensitized the breast cancer cells to the ionizing radiation and inhibited the radiation-induced migration and the release of MMP2 and MMP9. Lipoic acid also prevented the TGFß1 release and inhibited the radiation-induced EMT in breast cancer cells. The inhibition of TGFß signaling by lipoic acid is associated with the inhibition of radiation-induced activation and translocation of NF-κB. These results suggest that α-lipoic acid inhibits the radiation-induced TGFß signaling and nuclear translocation of NF-κB, thereby inhibiting the radiation-induced EMT and sensitizing the breast cancer cells to ionizing radiation.