Connexin26 expression is associated with lymphatic vessel invasion and poor prognosis in human breast cancer

Abstract

Purpose Cx26, which is a constituent of the connexin family, has recently been shown to promote metastasis through enhancing the vascular invasion in mouse melanoma cells. In this study, we have investigated whether or not Cx26 expression is associated with vascular invasion and recurrences in human breast cancers. Experimental design Cx26 expression was studied in 152 invasive breast cancers by immunohistochemistry. In order to investigate the blood vessel invasion and lymphatic vessel invasion with precision, immunohistochemical staining of blood vessels and lymphatic vessels was carried out using anti-CD34 and anti-D2-40 antibodies, respectively. Results Cx26 was positive in 51.3% (78/152) of the breast tumors. A statistically significant association was observed between Cx26 expression and large tumor size (P = 0.013) or high histological grade (P = 0.043). Frequency of blood vessel invasion was higher in Cx26-positive tumors (5.1%, 4/78) than in Cx26-negative tumors (1.4%, 1/74) though not statistically significant (P = 0.210). Lymphatic vessel invasion was significantly (P = 0.001) more frequent in Cx26-positive tumors (39.7%) than in Cx26-negative tumors (14.9%). Patients with Cx26-positive tumors showed a significantly (P < 0.001) poorer prognosis than those with Cx26-negative tumors. Multivariate analysis showed that Cx26 (P < 0.05) expression was an independent prognostic factor. Conclusions Cx26 expression is associated with lymphatic vessel invasion, large tumor size, high histological grade, and poor prognosis in human breast cancers. Cx26 seems to enhance the metastasis probably through promoting the lymphatic vessel invasion. Cx26 might be clinically useful as a new prognostic factor.

Connexins: a junctional crossroad to breast cancer

“…Moreover, a GJIC via Cx43 increased the adhesion of breast cancer cells to lung endothelial cells, whereas such adhesion was reduced in breast cancer cells with a dominant-negative Cx43 mutation, known to exhibit non-functional GJIC, highlighting the importance of Cx43 and GJIC in metastatic homing of breast cancer cells (Elzarrad et al, 2008). Other studies have correlated Cx26 expression to an increased lymphatic vessel invasion, large tumor size and poor prognosis in breast cancer patients (Naoi et al, 2007). Similarly, another group of researchers showed that Cx26 and Cx43 contributed to breast cancer metastasis to lymph nodes where their expression was upregulated when compared to primary tumors, with distinct localization of connexins to the membrane (Kanczuga-Koda et al, 2006).…”

Cx43 suppresses mammary tumor metastasis to the lung in a Cx43 mutant mouse model of human disease

“…Consistently, it has been shown that re-expression of connexins in breast tumor cell lines can result in a partial cell re-differentiation to a more normal phenotype (Hirschi et al, 1996;Kalra et al, 2006;McLachlan et al, 2007), whereas downregulation of connexins in breast cell lines render them more migratory and invasive . However, a few studies have also reported an upregulation of connexins in breast cancer (Jamieson et al, 1998;Kanczuga-Koda et al, 2006;Naoi et al, 2007). Finally, it has been suggested that the role of connexins may differ depending of the type of tumor or its stage of progression, even favouring metastasis (McLachlan et al, 2007;Naus and Laird, 2010).…”

Clinical Significance of Detecting Lymphatic and Blood Vessel Invasion in Stage II Colon Cancer Using Markers D2-40 and CD34 in Combination

“…Therefore, it is suggested that for early phase post-surgery colon cancer samples, immunohistochemistry with anti-D2-40 and anti-CD34 monoclonal antibodies, which is simple and affordable, shall be routinely performed to detect LVI and BVI (Van den Eynden et al, 2006;Naoi et al, 2007).…”