Overexpression of Calreticulin in Malignant and Benign Breast Tumors: Relationship with Humoral Immunity

Abstract

Objective: Calreticulin is a multicompartmental protein which regulates many important cellular responses. The aim of this study was to elucidate whether the intensity and location of calreticulin overexpression in tumor cells are related to the elevated humoral immunity to calreticulin in patients with benign or malignant breast disease. Methods: This study involved 27 patients with benign and 58 patients with malignant breast tumors before surgical resection and 38 healthy volunteers. Cytoplasmatic or membranous calreticulin overexpression in malignant or benign cells in paraffin-embedded tissues was determined using immunohistochemistry. Levels of the serum anti-calreticulin autoantibodies were detected by ELISA. Results: Statistically significant differences between serum levels of IgA of anti-calreticulin antibodies in controls and patients with breast tumors, and between controls and patients with nonmalignant breast diseases were found, but no statistically significant differences were found between levels of serum IgG anti-calreticulin antibodies. Humoral immunity to calreticulin developed against cytoplasmatic and co-localized membranous calreticulin was not correlated to the intensity of its overexpression and was present even in the absence of its membranous localization. Conclusions: The degree of calreticulin overexpression in lobular breast carcinoma is lower than in ductal breast carcinoma. Elevated concentrations of anti-calreticulin IgA antibodies were present more frequently in patients with metastasis in locoregional lymph nodes in comparison to anti-calreticulin IgG antibodies.

Detection of tumor-associated antigens in culture supernatants using autoantibodiesin sera from patients with bladder cancer

“…Although calreticulin overexpression in tumor cells is well known, the mechanism of this increase have not been well defined. Previous studies reported an elevated serum IgG level of anticalreticulin AAb in patients from hepatocellular carcinoma, gallbladder adenocarcinoma, pancreatic adenocarcinoma, and breast cancer when compared to healthy controls (10,34). These data are concordant with our present results, suggesting that humoral immunity against calreticulin may be associated with the overexpression of calreticulin.…”

Contribution of humoral immune responses to the antitumor effects mediated by anthracyclines

“…[47][48][49][50] Interestingly, anti-CRT IgA titers are more useful than anti-CRT IgG levels for detecting mammary, colorectal, hepatocellular and pancreatic carcinomas, alcoholic hepatitis, refractory celiac disease or primary biliary cirrhosis. 30,[51][52][53] High concentrations of anti-CRT IgA antibodies were more frequently detected in lymph node-positive breast cancers than IgG antibodies, but failed to correlate with CRT membrane expression. 30 The biological significance of anti-CRT antibodies is unclear.…”

“…30,[51][52][53] High concentrations of anti-CRT IgA antibodies were more frequently detected in lymph node-positive breast cancers than IgG antibodies, but failed to correlate with CRT membrane expression. 30 The biological significance of anti-CRT antibodies is unclear. However, experimental immunization against CRT could induce liver focal necrosis and hepatitis.…”

“…Paired serum specimens were available in four cases, revealing no specific increase post therapy (Supplementary Figure 3). The seroconversion (defined as antibody titers reaching levels above the detection threshold of the ELISA test 30 ) of patients either at diagnosis or after neoadjuvant chemotherapy failed to correlate with the pathological complete responses (Figure 6c) or metastases-free survival (Figure 6d). We conclude that in human breast cancer, humoral immune responses directed against CRT lack clinical significance.…”

“…29 Its immunohistochemical detection in paraffin-embedded primary breast cancer tissues has been correlated with serum levels of anti-CRT antibodies. 30 We analyzed the titers of IgA and IgG antibodies in 75 healthy controls and 63 breast cancer patients (Table 1, Figure 6a) at diagnosis, during and after systemic chemotherapy (Figure 6b). Both anti-CRT IgA and IgG serum levels were slightly higher in (Figure 6a).…”