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

Overview

Journal Breast Cancer Res

Specialty Oncology

Date 2010 Jul 15

PMID 20626886

Citations 127

Authors

Hazem Ghebeh

Cynthia Lehe

Eman Barhoush

Khaldoon Al-Romaih

Asma Tulbah

Monther Al-Alwan

Siti-Faujiah Hendrayani

Pulicat Manogaran

Ayodele Alaiya

Taher Al-Tweigeri

Abdelilah Aboussekhra

Said Dermime

Affiliations

Soon will be listed here.

Abstract

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.

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