Multi-step process of human breast carcinogenesis: A role for BRCA1, BECN1, CCND1, PTEN and UVRAG

Abstract

Abstract. In the female population in Asia, systematic investigation concerning alterations in cancer-related genes in breast carcinoma is rare, and the correlation among oncogene or suppressor gene expression with tumor cell apoptosis, cell cycle regulation and tumor cell autophagy remains to be clarified. In this study, a tissue microarray consisting of 360 individual samples from three different breast tissues was generated. By comparing the expression of the tumor-suppressor genes (BRCA1, BECN1, CCND1, PTEN and UVRAG) in ductal breast cancer and normal breast tissues, respectively, we were able to assign changes in the expression of these mRNAs to specific stages and allocate them to define the roles in the multi-step process of breast carcinogenesis. Tumor-suppressor genes, such as BRCA1 and BECN1, usually had lower signals in the carcinomatous tissues (10.2 and 6.6%) compared to the normal tissues (31 and 32.6%), while stronger positive dots (positive cells >30%) usually existed in the normal tissues. The patients in the oldest age group had the lowest expression rate. Only BECN1 and CCND1 expression showed a significant association with patient age (p= 0.030 and p= 0.003). A significant association was observed between BRCA1 and BECN1 expression and tumor size (p= 0.028 and p= 0.021). BECN1 gene expression was positively correlated with UVRAG and PTEN expression (p=0.006 and p=0.000). CCND1 was negatively correlated with PTEN, BECN1 and BRCA1 expression (p= 0.011, p= 0.000 and p= 0.000). Abnormal expression of BRCA1, BECN1, CCND1, PTEN and UVRAG may play a role in human breast carcinogenesis through dysregulated mRNA expression. Overexpressed CCND1 may shorten the G1 phase of the cell cycle, suppress cell apoptosis and contribute to the formation of invasive ductal carcinoma (IDC).

The Roles of Beclin 1 Expression in Gastric Cancer: A Marker for Carcinogenesis, Aggressive Behaviors and Favorable Prognosis, and a Target of Gene Therapy

“…In combination of these findings, we speculated that the regulatory correlation between Beclin 1 and E-cadherin depended on the cell types. Reportedly, loss and down-regulation of Beclin 1 expression was immunohistochemically observed in esophageal adenocarcinoma (64), colorectal cancer (65), breast cancer (66), but versa in pancreatic cancer (67). Here, we performed meta-analysis and found that down-regulated Beclin 1 expression in gastric cancer was positively linked to lymph node metastasis, TNM staging, dedifferentiation and poor prognosis, in agreement with our bioinformatics findings.…”

Decreased BECN1 mRNA Expression in Human Breast Cancer is Associated With Estrogen Receptor-Negative Subtypes and Poor Prognosis

“…Our findings are consistent with earlier studies of BECN1 in small cohorts of patients with breast cancer. Levels of BECN1 mRNA expression have been reported to be reduced in breast cancer ( Li et al, 2010 , Wu et al, 2012b ) and have been associated with poor differentiation, and increased tumor size, proliferation and risk of metastasis ( Wu et al, 2012b , Yao et al, 2011 ). In small datasets, low BECN1 mRNA expression was associated with triple-negative breast cancer ( Cicchini et al, 2014 ) and with worse prognosis regardless of ER status ( Perou et al, 2000 , Dong et al, 2013 ).…”

Role and mechanism of autophagy‐regulating factors in tumorigenesis and drug resistance

“…It is a phosphatase that acts as a tumor suppressor by inhibiting the PI3K/AKT signaling pathway. PI3K is essential for the activation of AKT; a serine/threonine kinase necessary for cell survival and growth 100,101 . PTEN along with other tumor suppressor genes like BRCA1 , BECN1 and UVRAG lead to the development of human breast cancer via dysregulated expression of mRNA 100 .…”