Genome-wide profiling of AP-1-regulated transcription provides insights into the invasiveness of triple-negative breast cancer.
Triple-negative breast cancer (TNBC) is an aggressive clinical subtype accounting for up to 20% of all breast cancers, but its malignant determinants remain largely undefined. Here, we show that in TNBC the overexpression of Fra-1, a component of the transcription factor AP-1, offers prognostic potential. Fra-1 depletion or its heterodimeric partner c-Jun inhibits the proliferative and invasive phenotypes of TNBC cells in vitro. Similarly, RNAi-mediated attenuation of Fra-1 or c-Jun reduced cellular invasion in vivo in a zebrafish tumor xenograft model. Exploring the AP-1 cistrome and the AP-1-regulated transcriptome, we obtained insights into the transcriptional regulatory networks of AP-1 in TNBC cells. Among the direct targets identified for Fra-1/c-Jun involved in proliferation, adhesion, and cell-cell contact, we found that AP-1 repressed the expression of E-cadherin by transcriptional upregulation of ZEB2 to stimulate cell invasion. Overall, this work illuminates the pathways through which TNBC cells acquire invasive and proliferative properties.
Authors' Affiliations: Department of Biosciences and Nutrition, Novum, Karolinska Institute, Huddinge; chunyan.zhao@ki.se karin.dahlman-wright@ki.se.
Chunyan
C
Zhao
Authors' Affiliations: Department of Biosciences and Nutrition, Novum, Karolinska Institute, Huddinge;
Yichun
Y
Qiao
Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas; and.
Philip
P
Jonsson
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm;
Jian
J
Wang
Authors' Affiliations: Department of Biosciences and Nutrition, Novum, Karolinska Institute, Huddinge;
Li
L
Xu
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm;
Pegah
P
Rouhi
Authors' Affiliations: Department of Biosciences and Nutrition, Novum, Karolinska Institute, Huddinge;
Indranil
I
Sinha
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm; Department of Medicine and Health Sciences, Linköping University, Linköping; Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, United Kingdom.
Yihai
Y
Cao
Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas; and.
Cecilia
C
Williams
Authors' Affiliations: Department of Biosciences and Nutrition, Novum, Karolinska Institute, Huddinge; Science for Life Laboratory, Karolinska Institute, Solna, Sweden; chunyan.zhao@ki.se karin.dahlman-wright@ki.se.
Karin
K
Dahlman-Wright
D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D018295:Neoplasms, Basal Cell; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D059467:Transcriptome; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000074165:Zinc Finger E-box Binding Homeobox 2; D000099169:Fos-Related Antigen 1
D015820:Cadherins; D018398:Homeodomain Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012097:Repressor Proteins; D018808:Transcription Factor AP-1; D000074165:Zinc Finger E-box Binding Homeobox 2; D000099169:Fos-Related Antigen 1; C492363:ZEB2 protein, human