Abstract
Fra-1 is a member of the Fos transcription factor family that is highly expressed in multiple cancers, playing important roles in transformation, proliferation, and metastasis. In this study, we observed an inverse correlation between the expression of Fra-1 in human stage II breast cancer tissues and the corresponding level of clinical chemoresistance. Extending these findings in vitro, we found that knockdown of Fra-1 in breast tumor cells was sufficient to confer resistance to doxorubicin and cyclophosphamide, whereas enhanced Fra-1 expression could render these cells chemosensitive. The tumor cell side population, which is enriched for cancer stem cells, was found to be associated with chemoresistance. Increased side population fractions were detected among tumor cell lines subjected to Fra-1 knockdown. In contrast, enhanced expression of Fra-1 was correlated with a decreased side population fraction, and significantly, this finding was recapitulated in vivo, where tumors with enhanced expression of Fra-1 were found to have blunted growth. Tumor cells subjected to Fra-1 knockdown grew faster and were larger in size. Taken together, our findings suggest that Fra-1 may be an important prognostic marker for breast cancer therapy.
Highlights
Chemotherapy has become a routine therapeutic approach for the treatment of cancer, with significant impact on patient survival
When we directly tested the function of Fra-1 in breast cancer stem cells (CSC), we found that suppression of Fra-1 expression correlated with both an increase in tumor CSCs and a concurrent increase in chemoresistance, whereas ectopic Fra-1 expression correlated with decreased incidence of CSCs and increased chemosensitivity of murine breast cancer cells
We evaluated the expression of transcription factor Fra-1 within a panel of 63 paraffin-embedded tissue samples from patients with stage II breast cancer who received chemotherapy following tumor resection by immunohistochemistry
Summary
Chemotherapy has become a routine therapeutic approach for the treatment of cancer, with significant impact on patient survival. The cancer stem cell hypothesis suggests that a small population of cells within a tumor will tend to share some common features with stem or progenitor cells, including self-renewal and differentiation These cancer stem cells (CSC) are thought to be responsible for primary tumorigenesis, and for resistance to chemotherapy and subsequent cancer recurrence. When we directly tested the function of Fra-1 in breast CSCs, we found that suppression of Fra-1 expression correlated with both an increase in tumor CSCs and a concurrent increase in chemoresistance, whereas ectopic Fra-1 expression correlated with decreased incidence of CSCs and increased chemosensitivity of murine breast cancer cells Together, these results suggest a novel role for Fra-1 in cancer biology, and raise the possibility that Fra-1 may be a significant prognostic response marker for tumor therapy
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