Breast cancer, autoantibodies and autoimmune inflammation

Chronic inflammation is a contributing cause for many cancers, and research recently published in BMC Cancer presents evidence that autoimmune inflammation may contribute to breast cancer by demonstrating the presence of autoantibodies directly involved in breast cancer development.

Similarities between breast cancer and autoimmune diseases

The authors state:

"Our studies on autoantibodies in malignancies strongly suggested that cancer sera exhibit immunologic features that are common in the rheumatic autoimmune diseases [ADs]. We have shown that anti-collagen antibodies and antinuclear antibodies [ANA] are found in the sera from lung cancer and head and neck cancer patients as frequently as in the systemic ADs such as rheumatoid arthritis [RA] and systemic lupus erythematosus [SLE]. With the use of molecular techniques and high throughput analyses, we and others have clearly shown that autoantibody classifiers have been constructed with high sensitivity and specificity for the diagnosis of breast and other cancers."

Predictive antibodies

Autoantibodies can appear years before the condition evolves to an easily recognized clinical entity.

"It is well known that autoantibodies (such ANAs in SLE and rheumatoid factors and anti-cyclic citrullinated peptides antibodies in RA) can be detected many years before the onset of these ADs. We and others have also found autoantibodies in the sera of patients with cancer before clinical diagnosis, notably suggesting that the breakdown of tolerance to tumor antigens is an early event in carcinogenesis. The diagnostic value of autoantibodies as immune biomarkers in the systemic and organ-specific ADs such as SLE, RA, scleroderma, and primary biliary cirrhosis [PBC] is well established."

Although anti-nuclear antibodies (ANAs) have been recognized in breast cancer sera for many years there has been no comprehensive study of autoantibodies in the sera of a large cohort of patients with pathology-proven breast cancer. So...

"The objective of this work was to demonstrate that the autoantibodies detected in BC sera have unique immunological features, resembling the model epitomized by the rheumatic and organ-specific ADs."

Autoantibodies clearly apparent in breast cancer

They used immunofluorescence on HEp-2 cells to survey autoantibodies in sera from women undergoing annual screening mammography with suspicious assessment and immunoblots of breast cancer proteins, crithidia luciliae assay for anti-dsDNA antibodies, and multiple ELISAs for extractable nuclear antigens [ENAs], anti-centromere antibodies [CENPs], and NSP1 antibodies and for the M2 component of pyruvate dehydrogenase. These included sera from 100 cases each of ductal carcinoma in situ [DCIS], invasive ductal carcinoma [IDC] of the breast and controls of benign breast disease [BBD]. The pathologic diagnoses of cases were made by breast biopsy. Autoantibodies were clearly present in the subjects with breast cancer:

"The combined use of IFA [immunofluorescence] on HEp-2 cells and IBs [immunoblots] of BC [breast cancer] proteins detected autoantibodies in virtually all sera from patients with breast cancer. IFA of BC and control sera revealed a spectrum of autoantibodies with maximal reactivity in sera from patients with IDC and decreasing reactivity in DCIS and BBD sera; minimal nuclear or cytoplasmic reactivity was shown in the sera from patients with OA and from healthy hospital nurses."

Moreover, they showed that autoantibodies in breast cancer sera have unique immunological features comparable to those found in rheumatic and organ-specific autoimmune diseases.

"We show here that autoantibodies reacting with antigens located in several important cell organelles (including mitochondria, centromeres, nucleoli, centrosomes, and the mitotic spindle) are consistently found in sera from women with suspicious mammography findings. The level of these autoantibodies was highest in women with IDC, lesser in women with DCIS, and still lower but above background levels in healthy women with BBD. Moreover, AMAs, anti-centromere, and anti-centrosome antibodies are not components of the autoantibody repertoire of normal healthy women."

Clincial implications for diagnosis and prevention of breast cancer

The authors note the diagnostic utility of breast cancer antibody profiles:

"These findings suggest that, in the future, the combination of suspicious mammography and autoantibody signatures could potentially identify a group of women in the early stages of breast carcinogenesis. Here we provide evidence that most of the antigens targeted by autoantibodies in BC sera differ from those involved in the rheumatic and organ-specific ADs."

Although autoantibodies and other screening methods are superseded by the ONCOblot test, this report is a valuable reminder for clinicians to thoroughly attend to low grade chronic inflammation and early stages of autoimmunity as a fundamental tactic in breast cancer prevention.Moreover, considering the current controversy regarding justification and potential harm associated with radical treatment of DCIS, investigating and treatment underlying autoimmune inflammatory factors presents a middle option between invasive therapy and doing nothing.The authors conclude:

"In this study, detection of autoantibodies in the sera from practically all women with breast cancer provides compelling evidence that an antigen-driven autoantibody response takes place in BC. Moreover, we report here that the autoantibody profile detected in BC sera has distinctive features, probably reflecting unique BC-associated antibody specificities targeting antigens in the mitochondria, the centrosomes, the spindle apparatus, the nucleoli, and the cytoskeleton."

Furthermore...

"The consistent finding of anti-centrosome antibodies in breast cancer sera is novel and supports the possibility that centrosome autoimmunity might be involved in cancer pathogenesis. Detection of AMAs, anti-centromere, anti-centrosome antibodies, and MNDs in a fraction of women with suspicious mammography findings and BBD indicates that the process triggering autoantibody formation starts in the pre-malignant phase. Our findings suggest the hypothesis that autoimmunity triggered by TAAs may inflict epithelial damage to the breast, promoting chronic inflammation and cancer progression; i.e., that BC may behave as an organ-specific AD triggered by multiple epithelial and other breast antigens."