Long non-coding NR2F1-AS1 is associated with tumor recurrence in estrogen receptor-positive breast cancers.

The tenacity of late recurrence of estrogen receptor (ER)-positive breast cancer remains a major clinical issue to overcome. The administration of endocrine therapies within the first 5 years substantially minimizes the risk of relapse; however, some tumors reappear 10-20 years after the initial diagnosis. Accumulating evidence has strengthened the notion that long noncoding RNAs (lncRNAs) are associated with cancer in various respects. Because lncRNAs may display high tissue/cell specificity, we hypothesized this might provide new insights to tumor recurrence. By comparing transcriptome profiles of 24 clinical primary tumors obtained from patients who developed distant metastases and patients with no signs of recurrence, we identified lncRNA NR2F1-AS1 whose expression was associated with tumor recurrence. We revealed the relationship between NR2F1-AS1 and the hormone receptor expressions in ER-positive breast cancer cells. Gain of function of NR2F1-AS1 steered cancer cells into quiescence-like state by the upregulation of dormancy inducers and pluripotency markers, and activates representative events of the metastatic cascade. Our findings implicated NR2F1-AS1 in the dynamics of tumor recurrence in ER-positive breast cancers and introduce a new biomarker that holds a therapeutic potential, providing favorable prospects to be translated into the clinical field.

MicroRNA-493-5p-mediated repression of the MYCN oncogene inhibits hepatic cancer cell growth and invasion.

Primary hepatic tumors mainly include hepatocellular carcinoma (HCC), which is one of the most frequent causes of cancer-related deaths worldwide. Thus far, HCC prognosis has remained extremely poor given the lack of effective treatments. Numerous studies have described the roles played by microRNAs (miRNAs) in cancer progression and the potential of these small noncoding RNAs for diagnostic or therapeutic applications. The current consensus supports the idea that direct repression of a wide range of oncogenes by a single key miRNA could critically affect the malignant properties of cancer cells in a synergistic manner. In this study, we aimed to investigate the oncogenes controlled by miR-493-5p, a major tumor suppressor miRNA that inactivates miR-483-3p oncomir in hepatic cancer cells. Using global gene expression analysis, we highlighted a set of candidate genes potentially regulated by miR-493-5p. In particular, the canonical MYCN protooncogene (MYCN) appeared to be an attractive target of miR-493-5p given its significant inhibition through 3'-UTR targeting in miR-493-5p-rescued HCC cells. We showed that MYCN was overexpressed in liver cancer cell lines and clinical samples from HCC patients. Notably, MYCN expression levels were inversely correlated with miR-493-5p in tumor tissues. We confirmed that MYCN knockdown mimicked the anticancer effect of miR-493-5p by inhibiting HCC cell growth and invasion, whereas MYCN rescue hindered miR-493-5p activity. In summary, miR-493-5p is a pivotal miRNA that modulates various oncogenes after its reexpression in liver cancer cells, suggesting that tumor suppressor miRNAs with a large spectrum of action could provide valuable tools for miRNA replacement therapies.

MiR-1285-5p/TMEM194A axis affects cell proliferation in breast cancer.

The onset of breast cancer among young patients is a major issue in cancer etiology. Our previous study has shown that poor prognosis in young women with breast cancer is associated with lower expression of the microRNA miR-1285-5p. In this study, we showed that the expression of miR-1285-5p is lower in tumor tissues than in normal tissues. Accumulating evidence suggests that miR-1285-5p plays critical roles in various types of cancers. However, the functional role of miR-1285-5p in breast cancer remains to be elucidated. Here, we showed the tumor-suppressive role of miR-1285-5p and detailed its mechanism of action in breast cancer. Overexpression of miR-1285-5p significantly inhibited cell proliferation in breast cancer cells regardless of the tumor subtype. Among the target genes of miR-1285-5p, we found that transmembrane protein 194A (TMEM194A) was directly regulated by miR-1285-5p. Notably, separation of centrosomes from the nuclear envelope was observed upon knockdown of TMEM194A or overexpression of miR-1285-5p. In conclusion, our findings show that miR-1285-5p is a tumor suppressor via TMEM194A inhibition in breast cancer.

Towards Circulating-Tumor DNA-Based Precision Medicine.

In the era of precision medicine, targeted therapies have been implemented for various diseases. Genomic information guides decision-making in cancer treatment. The improvements in next-generation sequencing and polymerase chain reaction have made it possible to access the genetic information using circulating-tumor DNAs (ctDNAs). Molecular characteristics of individual tumors can be obtained by analysis of ctDNAs, thus making them excellent tools to guide decision-making during treatment. In oncology, the use of ctDNAs in clinical practice is now gaining importance. Molecular analysis of ctDNAs has potential for multiple clinical applications, including early diagnosis, prognosis of disease, prognostic and/or predictive biomarkers, and monitoring response to therapy and clonal evolution. In this paper, we highlight the applications of ctDNAs in cancer management, especially in metastatic setting, and summarize recent studies about the use of ctDNAs as predictive biomarkers for the therapeutic adaptation/response in lung cancer, breast cancer, and colorectal cancer. These studies offer the evidence to use ctDNAs as a promising approach to solve unmet clinical needs.

Invasive breast cancers in adolescent and young adult women show more aggressive immunohistochemical and clinical features than those in women aged 40-44 years.

BACKGROUND: Limited knowledge exists concerning the clinicopathological features of breast cancers (BCs) occurring in adolescent and young adult (AYA) women. We evaluated tumor characteristics in AYA women in comparison with those in middle-aged premenopausal women. METHODS: From consecutive AYA patients (< 35-year-old) with invasive BC in a single institute, 82 patients first treated with surgery were examined. As the control group, 82 tumors from middle-aged premenopausal patients (40-44 years) were selected by matching pathological T and N factors. We compared habitual factors, immunohistochemical parameters, and patient outcome between the two groups. RESULTS: Most of the study population (148 of 164, 90.2%) were in the early clinical stages (stage I or II). In the AYA group, the number of childbirths was smaller (p < 0.0001), while the volume of alcohol consumption was larger (p < 0.0001), and palpable primary tumors were more frequent (p < 0.01) than in the control group. The positivities of estrogen receptor, progesterone receptor, and androgen receptor were lower (p < 0.001, p = 0.03, and p < 0.001, respectively), and the triple-negative (TN) BCs rates were higher (p < 0.01) in the AYA group. Distant recurrence-free survival (DRFS) curves were different in the whole population (p = 0.02) and in hormone receptor-positive cases (p = 0.01). CONCLUSIONS: We confirmed that BCs occurring in AYA women had more aggressive features than those of the older premenopausal women in terms of a high proportion of TN subtypes and a lower DRFS.

A tissue microRNA signature that predicts the prognosis of breast cancer in young women.

Since breast cancers in young women are generally aggressive, young patients tend to be intensively treated with anti-cancer drugs. To optimize the strategy for treatment, particularly in young women, prognostic biomarkers are urgently required. The objective of this study was to identify a tissue microRNA (miRNA) signature that predicts prognosis in young breast cancer patients. Total RNA from 45 breast cancer patients aged <35 years was extracted from formalin-fixed paraffin-embedded (FFPE) tissues and analyzed using miRNA microarrays. Patients were categorized into two groups according to recurrence status within the 5 year period after surgery: recurrence (n = 11) and non-recurrent (n = 34). Histological parameters of hormone receptors and Ki-67 were statistically compared between the two groups. Differentially expressed miRNAs were identified, and their associations with overall survival (OS) were evaluated by log-rank test. The median observation period was 5.8 years for the recurrent group, and 9.1 years for the non-recurrent group. Nine miRNAs were significantly differentially expressed between the recurrent and non-recurrent groups. Receiver Operating Characteristic curve analysis was performed to evaluate the prediction accuracy of the identified miRNAs, and the resultant area under the curve was >0.7. Five of the miRNAs were validated by qRT-PCR, and the expression levels of three of those five (miR-183-5p, miR-194-5p, and miR-1285-5p), both alone and in combination, were associated with OS. In conclusion, we identified three candidate miRNAs that could be used separately or in combination as prognostic biomarkers in young breast cancer patients. This miRNA signature may enable selection of better treatment choices for young women with this disease.