Brachyury, a vaccine target, is overexpressed in triple-negative breast cancer

Abstract

Patients diagnosed with triple negative breast cancer (TNBC) have a high rate of tumor metastasis and a poor prognosis. The treatment option for these patients is currently chemotherapy, which results in very low response rates. Strategies that exploit the immune system for the treatment of cancer have now shown the ability to improve survival in several tumor types. Identifying potential targets for immune therapeutic interventions is an important step in developing novel treatments for TNBC. In this study, in-silico analysis of publicly available datasets and immunohistochemical analysis of primary and metastatic tumor biopsies from TNBC patients were conducted to evaluate the expression of the transcription factor brachyury, a driver of tumor metastasis and resistance and a target for cancer vaccine approaches, in TNBC. Analysis of breast cancer datasets demonstrated a predominant expression of brachyury mRNA in TNBC and in basal vs. luminal or HER2 molecular breast cancer subtypes. At the protein level, variable levels of brachyury expression were detected both in primary and metastatic TNBC lesions, and a strong association was observed between nuclear brachyury protein expression and the stage of disease, with nuclear brachyury being more predominant in metastatic vs. primary tumors. Survival analysis also demonstrated an association between high levels of brachyury in the primary tumor and poor prognosis. Two brachyury-targeting cancer vaccines are currently undergoing clinical evaluation; the data presented here provides rationale for utilizing brachyury-targeting immunotherapy approaches for the treatment of TNBC.

Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the Transcription Factor Brachyury

“…Tumor cells undergoing this phenotypic transition exhibit enhanced motility and invasiveness in vitro , a propensity to metastasize in vivo , and features of tumor stemness (16), including resistance to a range of therapeutics such as chemotherapy, radiation, small molecule therapies, and, potentially, immunotherapy (17–20). In agreement with a role for brachyury in the progression of carcinomas, multiple studies have now shown that the level of brachyury in the primary tumor correlates with poor patient prognosis in carcinomas of the lung (21), colon (6), breast (9), triple-negative breast (10), and gastrointestinal stromal tumor (GIST) (22). Brachyury expression has also been shown to be correlated with advanced-stage prostate cancer (8).…”

“…Subsequent studies have found that brachyury is absent in most normal adult human tissues, with the exception of low levels found in normal testis, thyroid, and a subset of B cells (2,3). High levels of brachyury have been found, however, in the primary and/or metastatic sites of non-small cell lung cancer (NSCLC) and small cell lung cancer (4,5), colon (6), hepatocellular (7), prostate (8), and breast carcinomas (9), including triple-negative breast cancer (TNBC) (10). High levels of brachyury are also characteristic of chordoma (11,12), a rare tumor type thought to originate from remnants of the notochord where brachyury is normally found in the human embryo.…”

Expression of epithelial–mesenchymal transition driver brachyury and status of tumor-infiltrating CD8+ and FOXP3+ lymphocytes in predicting treatment responses to neoadjuvant chemotherapy of breast cancer

“…However, this expression was also statistically significantly related to ER+ status, in contrast to the findings of previous studies (p = 0.005). 25,38 An association between the subtypes of breast cancer and brachyury seems to be present, but there have been few studies on this topic, and further research is needed in the future. The brachyury index was highest in the NR group (mean = 171.7; SD = 67.9) and lowest in the pCR group (mean = 130.0; SD = 84.3), but this difference was not statistically significant (p = 0.625), although the finding might be related to the poor treatment outcome, similar to previous study results.…”

“…The brachyury index was calculated by multiplying the percentage of positive cells by the staining intensity. 25 …”

Pharmacological and immunological targeting of tumor mesenchymalization

“…Clinical evidence suggesting an association between tumor phenotypic transitions and cancer progression includes the results of multiple correlative studies demonstrating a positive association between the expression of mesenchymal markers (such as vimentin or N-cadherin) and/or the loss of epithelial E-cadherin in clinical samples with poor prognosis (Gravdal et al, 2007; Tan et al, 2014). Similarly, aberrant expression of transcriptional drivers of the mesenchymal phenotype, including SNAI1, SNAI2, brachyury, and others have been positively correlated with poor clinical outcome in a range of human tumor types (Blanco et al, 2002; Elloul et al, 2005; Gravdal et al , 2007; Hamilton et al, 2016b; Palena et al, 2014; Pinto et al, 2014). Direct evidence for a role of this phenomenon in tumor metastasis, however, originates from murine models of cancer.…”