Expression of cancer testis antigens in human BRCA-associated breast cancers: potential targets for immunoprevention?

Abstract

Introduction Novel breast cancer risk-reducing strategies for individuals with germline mutations of the BRCA1 and/or BRCA2 genes are urgently needed. Identification of antigenic targets that are expressed in early cancers, but absent in normal breast epithelium of these high-risk individuals, could provide the basis for the development of effective immunoprophylactic strategies. Cancer testis (CT) antigens are potential candidates because their expression is restricted to tumors, and accumulating data suggest that they play important roles in cellular proliferation, stem cell function, and carcinogenesis. The objective of this study was to examine the expression of CT antigens and their frequency in BRCA-associated breast cancers. Methods Archived breast cancer tissues (n = 26) as well as morphologically normal breast tissues (n = 7) from women carrying deleterious BRCA 1 and/or 2 mutations were obtained for antigen expression analysis by immunohistochemistry. Expression of the following CT antigens was examined: MAGE-A1, MAGE-A3, MAGE-A4, MAGE-C1. CT7, NY-ESO-1, MAGE-C2/CT10, and GAGE. Results CT antigens were expressed in 16/26 (61.5%, 95% CI 43–80%) of BRCA-associated cancers, including in situ tumors. Thirteen of twenty-six (50%) breast cancers expressed two or more CT antigens; three cancers expressed all seven CT antigens. MAGE-A was expressed in 13/26 (50%) of cancers, NY-ESO-1 was expressed in 10/26 (38%) of tumors. In contrast, none of the CT antigens were expressed in adjacent or contralateral normal breast epithelium (P = 0.003). Conclusions We report a high CT antigen expression rate in BRCA-associated breast cancer as well as the lack of expression of these antigens in benign breast tissue of carriers, identifying CT antigens as potential vaccine targets for breast cancer prevention in these high-risk individuals.

Proteomic Profiling of Triple-negative Breast Carcinomas in Combination With a Three-tier Orthogonal Technology Approach Identifies Mage-A4 as Potential Therapeutic Target in Estrogen Receptor Negative Breast Cancer

“…A number of studies have previously established the expression of CTAs in breast tumors, and in some cases CTA expression was shown to be associated with hormone-receptor negative breast cancers (41,(43)(44)(45)(46)(47)(48)(49). However, these studies reported mostly on MAGE gene expression rather than protein levels or on the expression of Mage protein families rather than on specific proteins.…”

Prognostic Value of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancers From Two Phase III Randomized Adjuvant Breast Cancer Trials: ECOG 2197 and ECOG 1199

“…In fact, cancer testis antigens such as MAGE-A3 and NY-ESO-1 are most prevalent in TNBCs, as demonstrated by several groups. 17,18 TILs at diagnosis therefore likely indicate an ongoing antitumor immune response, which can contribute to improved outcomes (as shown for other solid tumors 19,20 ), although underlying mechanisms such as increased response to cytotoxics (suggested by neoadjuvant study 3 ) and/or eradication of micrometastatic disease have not yet been fully investigated.…”

Potential Use of Vaccines in the Primary Prevention of Breast Cancer in High-Risk Patients

“…In 2011, Curigliano et al [30] More recently, the high expression of CT antigens mapping to chromosome X (CT-X) genes, including MAGE-A, has been correlated with worse survival in a multivariate analysis of 394 TN breast cancers [32]. Furthermore, Adams et al [33] reported a high incidence of CT antigen Table 1. Main criteria for a prophylactic (breast) cancer vaccination Therapeutic breast cancer vaccination against tumor-restricted antigens [3] Viral targets for prophylactic cancer vaccination [52] Self-targets for prophylactic breast cancer vaccination [67] -A sufficient number of immune cells with highly avid recognition of tumor antigens must be generated in vivo.…”

“…Under the selective pressure of vaccine-induced immune response, tumors may downmodulate the antigen resulting in antigen loss variants. Furthermore, since intracellular CT antigens are processed and presented by major histocompatibility complex (MHC) molecules for immune recognition, tumor downmodulation of MHC-I or the peptide-processing machinery could also hamper effective immunoprevention [33].…”