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B7-H4 overexpression contributes to poor prognosis and drug-resistance in triple-negative breast cancer

Authors
  • Wang, Ling1
  • Yang, Chao2
  • Liu, Xin-bo3
  • Wang, Li4
  • Kang, Fu-biao5
  • 1 the Third Hospital of Hebei Medical University, Department of Orthopedic Oncology, Shijiazhuang, Hebei, People’s Republic of China , Shijiazhuang (China)
  • 2 the Fourth Hospital of Hebei Medical University, Department of General Surgery, Shijiazhuang, Hebei, People’s Republic of China , Shijiazhuang (China)
  • 3 the Fourth Hospital of Hebei Medical University, Department of Thoracic Surgery, Shijiazhuang, Hebei, People’s Republic of China , Shijiazhuang (China)
  • 4 the Fourth Hospital of Shijiazhuang, Department of Pathology, Shijiazhuang, China , Shijiazhuang (China)
  • 5 Bethune International Peace Hospital, Department of Liver Diseases, Shijiazhuang, Hebei, People’s Republic of China , Shijiazhuang (China)
Type
Published Article
Journal
Cancer Cell International
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Jul 13, 2018
Volume
18
Issue
1
Identifiers
DOI: 10.1186/s12935-018-0597-9
Source
Springer Nature
Keywords
License
Green

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.

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