Doxorubicin downregulates cell surface B7-H1 expression and upregulates its nuclear expression in breast cancer cells: role of B7-H1 as an anti-apoptotic molecule

Breast Cancer Res. 2010;12(4):R48. doi: 10.1186/bcr2605. Epub 2010 Jul 13.


Introduction: B7-H1 (PD-L1, CD274) is a T cell inhibitory molecule expressed in many types of cancer, leading to immune escape of tumor cells. Indeed, in previous reports we have shown an association of B7-H1 expression with high-risk breast cancer patients.

Methods: In the current study, we used immunohistochemistry, immunofluorescence and Western blot techniques to investigate the effect of neoadjuvant chemotherapy on the expression of B7-H1 in breast cancer cells.

Results: Among tested chemotherapeutic agents, doxorubicin was the most effective in downregulating cell surface expression of B7-H1 in vitro. These results were validated in vivo in a xenograft mouse model, as well as in murine heart tissue known to constitutively express B7-H1. The doxorubicin-dependent cell surface downregulation of B7-H1 was accompanied by an upregulation of B7-H1 in the nucleus. This re-distribution of B7-H1 was concurrent with a similar translocation of phosphorylated AKT to the nucleus. Inhibition of the PI3K/AKT pathway abrogated the doxorubicin-mediated nuclear up-regulation of B7-H1, suggesting an involvement of PI3K/AKT pathway in the nuclear up-regulation of B7-H1. Interestingly, siRNA knock down of B7-H1 lead to an increase in spontaneous apoptosis, as well as doxorubicin-induced apoptosis, which indicates an anti-apoptotic role for B7-H1 in breast cancer cells. The novel discovery of B7-H1 expression in the nuclei of breast cancer cells suggests that B7-H1 has functions other than inhibition of T cells.

Conclusions: Our findings explain the previously reported immunomodulatory effect of anthracyclines on cancer cells, and provide a link between immunoresistance and chemoresistance. Finally these results suggest the use of dual combinatorial agents to inhibit B7-H1 beside chemotherapy, in breast cancer patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Apoptosis / drug effects*
  • B7-H1 Antigen
  • Blotting, Western
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cell Nucleus / metabolism*
  • Cell Proliferation / drug effects*
  • Down-Regulation / drug effects
  • Doxorubicin / pharmacology*
  • Female
  • Humans
  • Immunohistochemistry
  • Mammary Neoplasms, Experimental / drug therapy
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, Nude
  • Microscopy, Confocal
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Transport / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • Signal Transduction / drug effects
  • Up-Regulation / drug effects
  • Xenograft Model Antitumor Assays


  • Antibiotics, Antineoplastic
  • Antigens, CD
  • B7-H1 Antigen
  • CD274 protein, human
  • Doxorubicin
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt