Effects of Differential Distribution of Microvessel Density, Possibly Regulated by miR-374a, on Breast Cancer Prognosis

Abstract

Background: The discovery that microRNAs (miRNAs) regulate proliferation, invasion and metastasis provides a principal molecular basis of tumor heterogeneity. Microvessel distribution is an important characteristic of solid tumors, with significant hypoxia occurring in the center of tumors with low blood flow. The distribution of miR-374a in breast tumors was examined as a factor likely to be important in breast cancer progression. Methods: Breast tissue samples from 40 patients with breast cancer were classified into two groups: a highly invasive and metastatic group (HIMG) and a low-invasive and metastatic Group (LIMG). Samples were collected from the center and edge of each tumor. In each group, six specimens were examined by microRNA array, and the remaining 14 specimens were used for real-time RT-qPCR, Western blot and immunohistochemical analyses. Correlation analysis was performed for the miRNAs and target proteins. Follow-up was carried out during 28 months to 68 months after surgery, and survival data were analyzed. Results: In the LIMG, the relative content of miR-374a was lower in the center of the tumor than at its edge; in the HIMG, it was lower at the edge of the tumor, and miR-374a levels were lower in breast cancer tissues than in normal tissues. There was no difference between VEGF-A and VCAM-1 mRNA levels at the edge and center of the tumor; however, we observed a significant difference between VEGF-A and VCAM-1 protein expression levels in these two regions. There was a negative correlation between miR-374a and target protein levels. The microvessel density (MVD) was lower in the center of the tumor than at its edge in HIMG, but the LIMG vessels were uniformly distributed. There was a significant positive correlation between MVD and the number of lymph node metastases (Pearson correlation, r=0.912, P<0.01). The median follow-up time was 48.5 months. LIMG had higher rate of disease-free survival (100%, P=0.013) and longer median survival time (66 months) than HIMG, which had a lower rate of 75% and shorter median survival time (54 months). Conclusions: Our data demonstrated miR-374a to be differentially distributed in breast cancer; VEGF-A and VCAM-1 mRNA had coincident distribution, and the distribution of teh respective proteins was uneven and opposite to that for the miR-374a. These data might explain the differences in the distribution of MVD in breast cancer and variation in breast cancer prognosis.

Different types of tumor vessels in breast cancer: morphology and clinical value

“…We did not identify the relation of MVD with other clinical characteristics of BC. These results contradict the data of other authors that found an association of MVD with clinical characteristics and prognosis of BC (Li et al 2006 ; Popiela et al 2008 ; Fernández-Guinea et al 2013 ; Li et al 2013 ). We believe that the reason for these contradictions are due to the fact that in contrast to the above-mentioned authors in calculating of MVD we took into account only the normal microvessels, while the prognosis was associated with other types of tumor vessels.…”

“…However, its role in the progression of BC has been studied insufficiently and the received data are contradictory (Uzzan et al 2004 ). For example, several studies have indicated that a high microvessel density (MVD) in tumor is associated with more advanced stages and poor prognosis of BC (Popiela et al 2008 ; Fernández-Guinea et al 2013 ; Li et al 2013 ). At the same time, the other authors have found no association of MVD with clinical characteristics and long-term results of BC treatment (Fridman et al 2000 ; Gasparini 2001 ; Mohammed et al 2013 ).…”

Down-regulation of miRNA-452 is Associated with Adriamycin-resistance in Breast Cancer Cells

“…Recently dysregulated miRNAs have been reported that associated with every aspect of breast tumor biology, including tumor progression (Li et al, 2013a), apoptosis (Anaya-Ruiz et al, 2013), different distribution in clinicopathological subtypes (Li et al, 2013b), and acquisition of resistance to various chemotherapeutic agents. Causes of anti-cancer drug resistance are believed to be complex and current studies have indicated that the acquisition of chemotherapy drug resistance may also be modulated via the changes in miRNA levels.…”

miR-374a-CCND1-pPI3K/AKT-c-JUN feedback loop modulated by PDCD4 suppresses cell growth, metastasis, and sensitizes nasopharyngeal carcinoma to cisplatin

“…[7][8][9][10][11] It is likely that miR-374a serves a complex role in carcinogenesis that is context dependent.…”

“…In highly invasive and metastatic tumors, it was lower at the edges than that in the center, and lower in cancer tissues than in normal tissues. 11 Taken together, the functions and molecular basis of miR-374a are complex and contradictory, thus more studies are needed to confirm its context-specific role.…”