ABSTRACT
HER2-positive breast cancer is one of the most aggressive subtypes accounting for nearly 30% of diagnosed cases. It is associated with reduced disease-free survival, tumor invasiveness, and a poor overall prognosis. Unfortunately, numerous patients develop resistance to conventional therapies; therefore, many ongoing clinical trials are testing new possible treatments. Polyphenols are the main bioactive components of the Mediterranean diet with multiple beneficial properties playing a key role in cancer prevention through epigenetic regulation. Aberrant variations in microRNAs levels regulating oncogenes or tumor suppressor genes expression may lead to tumor development. Evidence has shown that dietary polyphenols modulate HER2-positive breast cancer-associated microRNAs, resulting in a reduction of tumor growth and metastatic potential, and chemosensitivity restoration without displaying toxicity-derived adverse effects. These beneficial properties make polyphenols a potential therapeutic approach for HER2-positive breast cancer patients in the clinical setting, alone or in combination with conventional therapies.
Subject(s)
Breast Neoplasms , MicroRNAs , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Epigenesis, Genetic , Epigenomics , Humans , MicroRNAs/genetics , Polyphenols/pharmacology , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolismABSTRACT
tRNA-derived fragments (tRFs) have been defined as a novel class of small noncoding RNAs. tRFs have been reported to be deregulated in cancer, but their biologic function remains to be fully understood. We have identified a new tRF (named tRF3E), derived from mature tRNAGlu, that is specifically expressed in healthy mammary glands but not in breast cancer (BC). Consistently, tRF3E levels significantly decrease in the blood of patients with epidermal growth factor receptor 2 (HER2)-positive BC reflecting tumor status (control > early cancer > metastatic cancer). tRF3E down-regulation was recapitulated in Δ16HER2 transgenic mice, representing a BC preclinical model. Pulldown assays, used to search for proteins capable to selectively bind tRF3E, have shown that this tRF specifically interacts with nucleolin (NCL), an RNA-binding protein overexpressed in BC and able to repress the translation of p53 mRNA. The binding properties of NCL-tRF3E complex, predicted in silico and analyzed by EMSA assays, are congruent with a competitive displacement of p53 mRNA by tRF3E, leading to an increased p53 expression and consequently to a modulation of cancer cell growth. Here, we provide evidence that tRF3E plays an important role in the pathogenesis of BC displaying tumor-suppressor functions through a NCL-mediated mechanism.-Falconi, M., Giangrossi, M., Elexpuru Zabaleta, M., Wang, J., Gambini, V., Tilio, M., Bencardino, D., Occhipinti, S., Belletti, B., Laudadio, E., Galeazzi, R., Marchini, C., Amici, A. A novel 3'-tRNAGlu-derived fragment acts as a tumor suppressor in breast cancer by targeting nucleolin.
Subject(s)
Breast Neoplasms/metabolism , Phosphoproteins/metabolism , RNA, Transfer, Glu/metabolism , RNA-Binding Proteins/metabolism , Animals , Blotting, Western , Breast Neoplasms/genetics , Electrophoretic Mobility Shift Assay , Gene Expression Regulation, Neoplastic/genetics , Gene Expression Regulation, Neoplastic/physiology , Humans , Mice , Mice, Transgenic , Phosphoproteins/genetics , RNA, Transfer, Glu/genetics , RNA-Binding Proteins/genetics , Reverse Transcriptase Polymerase Chain Reaction , NucleolinABSTRACT
BRCA1 and BRCA2 genes are involved in DNA double-strand break repair and related to breast cancer. Shift work is associated with biological clock alterations and with a higher risk of breast cancer. The aim of this study was to investigate the variability of expression of BRCA genes through the day in healthy subjects and to measure BRCA expression levels in shift workers. The study was approached in two ways. First, we examined diurnal variation of BRCA1 and BRCA2 genes in lymphocytes of 15 volunteers over a 24-hour period. Second, we measured the expression of these genes in lymphocytes from a group of shift and daytime workers. The change in 24-hour expression levels of BRCA1 and BRCA2 genes was statistically significant, decreasing from the peak at midday to the lowest level at midnight. Lower levels for both genes were found in shift workers compared to daytime workers. Diurnal variability of BRCA1 and BRCA2 expression suggests a relation of DNA double-strand break repair system with biological clock. Lower levels of BRCA1 and BRCA2 found in shift workers may be one of the potential factors related to the higher risk of breast cancer.
ABSTRACT
Basal-like breast cancer (BLBC) remains a great challenge because of its clinically aggressive nature and lack of effective targeted therapy. We analyzed the potential anti-neoplastic effects of sanguinarine, a natural benzophenanthridine alkaloid, against BLBC cells. Sanguinarine treatment resulted in a reduction of cell migration, in a dose-dependent inhibition of cell viability and in the induction of cell death by apoptosis in both human (MDA-MB-231 cells) and mouse (A17 cells) in vitro models of BLBC. In vivo experiments demonstrated that oral administration of sanguinarine reduced the development and growth of A17 transplantable tumors in FVB syngeneic mice. Western blotting analysis revealed that suppression of BLBC growth by sanguinarine was correlated with a concurrent upregulation of p27 and downregulation of cyclin D1 and with the inhibition of STAT3 activation. In addition, we identified sanguinarine as a potent inhibitor of dihydrofolate reductase (DHFR), able to impair enzyme activity even in methotrexate resistant MDA-MB-231 cells. These results provide evidence that sanguinarine is a promising anticancer drug for the treatment of BLBC.
