Abstract
BackgroundCancer/testis (CT) antigens are protein antigens normally expressed only in germ cells of testis, and yet are expressed in a proportion of a wide variety of human cancers. CT antigens can elicit spontaneous immune responses in cancer patients with CT-positive cancers, and CT antigen-based therapeutic cancer vaccine trials are ongoing for “CT-rich” tumors. Although some previous studies found breast cancer to be “CT-poor”, our recent analysis identified increased CT mRNA transcripts in the ER-negative subset of breast cancer.Methodology/Principal FindingsIn this study, we performed a comprehensive immunohistochemical study to investigate the protein expression of eight CT genes in 454 invasive ductal carcinomas, including 225 ER/PR/HER2-negative (triple-negative) carcinomas. We found significantly more frequent expression of all eight CT antigens in ER-negative cancers, and five of them—MAGEA, CT7, NY-ESO-1, CT10 and CT45, were expressed in 12–24% of ER-negative cancers, versus 2–6% of ER-positive cancers (p<0.001 to 0.003). In comparison, GAGE, SAGE1 and NXF2 were only expressed in 3–5% of ER-negative and 0–2% of ER-positive cancers. ER-negative cancers were also more likely to simultaneously co-express multiple CT antigens, with 27% (34/125) of ER-negative, CT-positive tumors expressing three or more CT antigens. HER2 status had no consistent effect on CT expression, and triple-negative carcinomas showed similar frequencies of MAGEA and NY-ESO-1 expression as ER-negative/HER2-positive carcinomas. More frequent CT expression was also found in tumors with higher nuclear grade (p<0.001 to p = 0.01) and larger in size (>2 cm).Conclusions/SignificanceCT antigens are preferentially expressed in hormone receptor-negative and high-grade breast cancer. Considering the limited treatment options for ER/PR/HER2 triple-negative breast cancer, the potential of CT-based immunotherapy should be explored.
Highlights
Cancer/testis (CT) antigens are protein antigens that are normally expressed in the germ cells of adult testis and developing fetal testis and ovary, but not in any other adult tissues
An exception was CT7, which is a cytoplasmic protein in normal germ cells but showed mixed cytoplasmic and nuclear distribution in most positive cases (Fig. 1C), with either nuclear (Fig. 1C) or cytoplasmic (Fig. 2E) compartment dominating
No statistical significant difference was observed in the extent/intensity distributions of CT expression between carcinomas of different estrogen receptor (ER) status, HER2 status, or other pathological parameters such as tumor size, nuclear grade or lymph node status
Summary
Cancer/testis (CT) antigens are protein antigens that are normally expressed in the germ cells of adult testis and developing fetal testis and ovary, but not in any other adult tissues. Examination of various types of human cancer showed CT gene activation and protein expression in a proportion of human cancers in a lineage-unrelated fashion [1,2,3,4] Due to this restricted pattern of expression, CT antigens are often recognized by the immune system of cancer patients, and this spontaneous immunogenicity raises the possibility of their use as therapeutic cancer vaccine targets. Few studies have evaluated CT expression in breast cancer, most of them focusing on the expression of NY-ESO-1 and MAGEA family [11,12,13,14,15] The data from these studies were highly variable, with the reported NY-ESO-1 positive rate between 2.1% to 40% in different immunohistochemical studies and MAGE-A positive rate between ,20% to 74%. Some previous studies found breast cancer to be ‘‘CT-poor’’, our recent analysis identified increased CT mRNA transcripts in the ER-negative subset of breast cancer
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