title: Fra-1 promotes breast cancer chemosensitivity by driving cancer stem cells from dormancy.
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.
authors.affiliation: School of Medicine, Nankai University, Tianjin, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Lu
authors.forename: Si
authors.initials: S
authors.lastname: Chen
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Tan
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Chenghu
authors.initials: C
authors.lastname: Liu
authors.forename: Zongjin
authors.initials: Z
authors.lastname: Li
authors.forename: Ze
authors.initials: Z
authors.lastname: Liu
authors.forename: Dwayne G
authors.initials: DG
authors.lastname: Stupack
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Reisfeld
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000494:pharmacology; D018450:Disease Progression; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000502:physiology*; D000099169:Fos-Related Antigen 1
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D003520:Cyclophosphamide; D004317:Doxorubicin; D016760:Proto-Oncogene Proteins c-fos; D000099169:Fos-Related Antigen 1