The Expression of the Nectin Complex in Human Breast Cancer and the Role of Nectin-3 in the Control of Tight Junctions during Metastasis

Abstract

IntroductionNectins are a family of integral protein molecules involved in the formation of functioning Adherens and Tight Junctions (TJ). Aberrant expression is associated with cancer progression but little is known how this effects changes in cell behaviour. This study aimed to ascertain the distribution of Nectins-1 to -4 in human breast cancer and the effect on junctional integrity of Nectin-3 modulation in human endothelial and breast cancer cells.MethodsA human breast tissue cohort was processed for Q-PCR and immunohistochemistry for analysis of Nectin-1/-2/-3/-4. Nectin-3 over-expression was induced in the human breast cancer cell line MDA-MB-231 and the human endothelial cell line HECV. Functional testing was carried out to ascertain changes in cell behaviour.ResultsQ-PCR revealed a distinct reduction in node positive tumours and in patients with poor outcome. There was increased expression of Nectin-1/-2 in patients with metastatic disease, Nectin-3/-4 was reduced. IHC revealed that Nectin-3 expression showed clear changes in distribution between normal and cancerous cells. Nectin-3 over-expression in MDA-MB-231 cells showed reduced invasion and migration even when treated with HGF. Changes in barrier function resulted in MDAN3 cells showing less change in resistance after 2h treatment with HGF (p<0.001). Nectin-3 transformed endothelial cells were significantly more adhesive, irrespective of treatment with HGF (p<0.05) and had reduced growth. Barrier function revealed that transformed HECV cells had significantly tighter junctions that wildtype cells when treated with HGF (p<0.0001). HGF-induced changes in permeability were also reduced. Overexpression of Nectin-3 produced endothelial cells with significantly reduced ability to form tubules (p<0.0001). Immunoprecipitation studies discovered hitherto novel associations for Nectin-3. Moreover, HGF appeared to exert an effect on Nectin-3 via tyrosine and threonine phosphorylation.ConclusionsNectin-3 may be a key component in the formation of cell junctions and be a putative suppressor molecule to the invasion of breast cancer cells.

Nectin‐2 in ovarian cancer: How is it expressed and what might be its functional role?

“…By using expression profile analysis, the authors showed overexpression of Nectin‐2 in ovarian cancer tissue as compared to healthy controls. Moreover, recent studies have shown that Nectin‐2 is highly expressed in epithelial malignancies and it was suspected that the expression correlates with high malignancy, fast progression, and/or poor prognosis of human breast cancer or gallbladder cancer . It was also demonstrated that inhibition of Nectin‐2—using monoclonal antibodies—suppressed tumor cell proliferation in vitro .…”

“…These functions of Nectin‐2 implicate its possible role in tumor cell survival and proliferation. So far, although only few investigations exist, the involvement of Nectin‐2 in tumor pathogenesis has been described for different tumor entities, such as breast and ovarian cancer, but also for gallbladder, colorectal or pancreatic cancer . In some of these studies, high expression of Nectin‐2 was associated with high malignancy, advanced tumor stage, poor differentiation, fast progression and poor outcome/prognosis .…”

Serum nectin-2 levels are diagnostic and prognostic in patients with colorectal carcinoma

“…In CRC, early diagnosis of primary and (Table 7). Nectins are immunoglobulin-like cell adhesion molecules which have been indicated to play a key role in roles such as cell movement, differentiation, reproduction, cellular polarization and cell survival [28,29]. It has been stated that each of them were expressed from various organs and the epithelial and endothelial cells of their tumors [13].…”

Cooperative Roles of Nectins with Cadherins in Physiological and Pathological Processes

“…The expression of nectin-2 is upregulated in hepatocellular carcinoma tissues (Kurokawa et al 2006), squamous cell/adenosquamous carcinomas and adenocarcinoma tissues of gallbladder (Miao et al 2013), and breast and ovarian carcinoma tissues (Oshima et al 2013). The expression of nectin-3 is downregulated in metastatic breast cancer tissues (Martin et al 2013). On the other hand, the expression of nectin-3 is upregulated in lung adenocarcinoma (Maniwa et al 2012) and ovarian, colorectal, and peritoneal endometriotic tissues (Ballester et al 2012).…”