Abstract
PurposeTriple-negative breast cancer (TNBC) has aggressive characteristics and fewer treatment options than other subtypes. The purpose of this study was to explore prognostic biomarkers for TNBC that can be easily detected from the blood samples.MethodsMDA-MB-231 and MDA-MB-231BR, a brain metastatic variant of the human TNBC cell line MDA-MB-231, were used as less and more aggressive models of TNBC, respectively. The extent to which the candidate gene/protein identified by RNA sequencing correlated well with aggressiveness of TNBC and how much protein was detected from the blood of tumor-bearing mice were evaluated.ResultsBoth the in vitro proliferation and in vivo tumor growth of MDA-MB-231BR were more rapid than those of MDA-MB-231. RNA sequencing identified ESM1 as a gene that was expressed significantly more in MDA-MB-231BR than in MDA-MB-231, and qRT-PCR confirmed a significantly higher expression of ESM1 in MDA-MB-231BR xenograft in vivo. Furthermore, Kaplan–Meier analysis of relapse-free survival demonstrated that TNBC patients with high ESM1 expression had clearly worse relapse-free survival than those with low ESM1 expression, which was consistent with our preclinical findings. Endocan, a protein of ESM1 gene product, was successfully detected in both conditioned medium from MDA-MB-231BR and plasma samples from mice bearing MDA-MB-231BR xenograft, which showed a significantly distinct pattern from less aggressive MDA-MB-231. Moreover, bisulfite sequence analysis revealed that overexpression of ESM1 in MDA-MB-231BR might be attributed to DNA demethylation in an upstream region of the ESM1 gene.ConclusionThis study indicates that endocan could be used as a blood-based prognostic biomarker in TNBC patients.
Highlights
Triple-negative breast cancer (TNBC) poses a serious problem in women who are, in particular, young [1], African-American, or have BRCA1 gene mutations [2,3,4], due to its aggressive characteristics as well as lack of targeted therapy
Kaplan–Meier analysis of relapse-free survival demonstrated that TNBC patients with high ESM1 expression had clearly worse relapse-free survival than those with low ESM1 expression, which was consistent with our preclinical findings
Bisulfite sequence analysis revealed that overexpression of ESM1 in MDA-MB-231BR might be attributed to DNA demethylation in an upstream region of the ESM1 gene
Summary
Triple-negative breast cancer (TNBC) poses a serious problem in women who are, in particular, young [1], African-American, or have BRCA1 gene mutations [2,3,4], due to its aggressive characteristics as well as lack of targeted therapy. Human epidermal growth factor receptor type 2 (HER2)-positive breast cancers have a poor prognosis [5], the development of therapeutic monoclonal antibodies against HER2 receptor has drastically improved the prognosis of such breast cancers. TNBC patients, do not always have a poor prognosis and, predicting the prognosis of TNBC patients prior to treatment would be of value in assessing the future condition of TNBC patients and their quality of life. Biopsy of the tumor and subsequent histological analysis can help to determine the subtype of breast cancer, the therapeutic regimen, and possibly the prognosis [6, 7]. It would be desirable to foresee the prognosis of TNBC patients through the use of a more patient-friendly technique, such as blood withdrawal
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