Abstract
BackgroundThe expression of the immunoregulatory protein B7-H4 has been reported in many types of cancer, including breast cancer. However, its role in triple-negative breast cancer (TNBC), especially its correlation with patients’ prognosis and chemoresistance remains unclear.MethodsThe expression of B7-H4 in TNBC tissues and cell lines were measured with Real-Time PCR and western blotting. 65 cases of TNBC tissue samples and adjacent non-tumor tissue samples were analyzed by immunochemistry to demonstrate the correlation between the B7-H4 expression and clinicopathological characteristics. In vitro studies assessed mAb MIH43 alone and in combination with transfecting B7-H4 siRNA on the growth of chemosensitive and chemoresistant TNBC cell lines by CCK-8 and apoptotic enzyme-linked immunosorbent assay (ELISA).ResultsB7-H4 expression was detected positive in 59 of 65 (90.8%) different stage TNBC patients, especially in the samples of recurrence TNBC patients after receiving neoadjuvant chemotherapy treatment. Survival curves showed that patients with B7-H4 overexpression had significantly shorter survival and recurrence time than those with low B7-H4 expression (p < 0.005). Univariate and multivariate COX regression analysis demonstrated that B7-H4 was an independent predictor for advanced tumor stage. The monoclonal antibody of B7-H4 has the potential anti-proliferative effects on inhibiting the chemoresistant TNBC cell lines and increasing the sensitivity of TNBC cell lines to doxorubicin, paclitaxel or carboplatin. RNAi-mediated silencing of B7-H4 in TNBC cells enhanced drug-induced apoptosis via inhibiting PTEN/PI3K/AKT pathway, whereas reexpression of B7-H4 in B7-H4 knockdown and low B7-H4 expressing cells increased the phosphorylation of PI3K and AKT along with restoration of PETN expression.ConclusionsOur data show that B7-H4 is a biomarker indicative of a poor prognosis in TNBC patients and at least partially downregulated in chemoresistance via PTEN/PI3K/AKT pathway. Targeting B7-H4 might provide an attractive therapeutic approach specifically for TNBC patients.
Highlights
The expression of the immunoregulatory protein B7-H4 has been reported in many types of can‐ cer, including breast cancer
Elevated B7‐H4 expression associated with human triple-negative breast cancer (TNBC) progression To evaluate the expression of B7-H4 in human TNBC, we used the publicly available cancer microarray database to estimate the status of B7-H4 transcript
Following RNA extraction, qRT-PCR confirmed the high presence of B7-H4 mRNA in all these TNBC samples with transcript levels, and MDA-MB-435 cells showed baseline high B7-H4 expression among all the tested cells (Fig. 1b, c)
Summary
The expression of the immunoregulatory protein B7-H4 has been reported in many types of can‐ cer, including breast cancer. There is increasing evidence showed that adding targeted therapies to adjuvant chemotherapy may increase the sensitivity of residual disease, which will reduce the dose of chemotherapy necessary to kill the remaining tumor cells, thereby minimizing the toxicity of the prolonged treatment [5, 6]. Upregulation of immune inhibitory molecules such as co-regulatory ligands/receptors and tolerogenic enzymes by cancer cells allow tumors escape from immune attack [7, 8]. Immune checkpoint inhibitors such as PD-1 and CTLA-4 have shown prominent and durable responses in diverse malignancies [9, 10]. Whether and how the engagement of B7-H4 by counter molecules affects the fate of B7-H4-expressing cells is poorly understood
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