cyanidin-3-o-beta-glucopyranoside and Triple-Negative-Breast-Neoplasms

Triple-negative breast cancer (TNBC) is a heterogeneous group of breast cancer with one common feature: distinctly metastatic nature with higher rate of relapse and shorter survival compared with other subtypes of breast cancer. The epithelial to mesenchymal transition (EMT) is highly associated with cancer metastasis. Cyanidin-3-glucoside (C3G), the most abundant anthocyanin pigment enriched in fresh fruits and vegetables, showed ideal anti-oxidant property. C3G could also inhibit certain malignant behaviors of cancer cells, however, whether repression of EMT was involved in its anti-cancer especially TNBC effect remains unknown. Herein, we report that C3G decreases the migratory and invasive nature of TNBC lines MDA-MB-231 and BT-549. Mechanistically, C3G induces reversion of EMT characterized by phenotype modulation with increased epithelial marker E-ca and ZO-1, decreased mesenchymal marker Vimentin, N-ca and EMT-associated transcription factors Snail1, Snail2. NF-κB is pivotal for EMT and Sirt1 is a NF-κB inhibitor. We show that NF-κB is attenuated and Sirt1 is induced by C3G in TNBC, respectively. And later evidence demonstrates that abrogation of Sirt1 with small interfering RNA transfection abolished NF-κB inhibition and EMT reversion by C3G. Subsequently, we show that microRNA-138(miR-138) represses Sirt1 via mRNA translation inhibition and is inhibited by C3G. Moreover, miR-138 repression is involved in Sirt1 re-activation and migratory and invasive inhibition of TNBC by C3G. Taken together, we supplied more evidence to the anti-breast cancer mechanisms of C3G.

Topics: Anthocyanins; Antigens, CD; Cadherins; Cell Line, Tumor; Cell Movement; Epithelial-Mesenchymal Transition; Female; Glucosides; Humans; MicroRNAs; NF-kappa B; Signal Transduction; Sirtuin 1; Snail Family Transcription Factors; Triple Negative Breast Neoplasms; Vimentin; Zonula Occludens-1 Protein

Anthocyanins have been shown to inhibit the growth and metastatic potential of breast cancer (BC) cells. However, the effects of individual anthocyanins on triple-negative breast cancer (TNBC) have not yet been studied. In this study, we found that cyanidin-3-o-glucoside (Cy-3-glu) preferentially promotes the apoptosis of TNBC cells, which co-express the estrogen receptor alpha 36 (ERα36) and the epidermal growth factor receptor (EGFR). We demonstrated that Cy-3-glu directly binds to the ligand-binding domain (LBD) of ERα36, inhibits EGFR/AKT signaling, and promotes EGFR degradation. We also confirmed the therapeutic efficacy of Cy-3-glu on TNBC in the xenograft mouse model. Our data indicates that Cy-3-glu could be a novel preventive/therapeutic agent against the TNBC co-expressed ERα36/EGFR.

Topics: Animals; Anthocyanins; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; ErbB Receptors; Estrogen Receptor alpha; Female; Gene Expression Regulation, Neoplastic; Glucosides; Humans; MCF-7 Cells; Mice; Mice, Inbred BALB C; Microcirculation; Mitochondria; Neoplasm Transplantation; Oligonucleotide Array Sequence Analysis; Protein Binding; Proto-Oncogene Proteins c-akt; Superoxide Dismutase; Triple Negative Breast Neoplasms