c-Jun induces mammary epithelial cellular invasion and breast cancer stem cell expansion.
The molecular mechanisms governing breast tumor cellular self-renewal contribute to breast cancer progression and therapeutic resistance. The ErbB2 oncogene is overexpressed in approximately 30% of human breast cancers. c-Jun, the first cellular proto-oncogene, is overexpressed in human breast cancer. However, the role of endogenous c-Jun in mammary tumor progression is unknown. Herein, transgenic mice expressing the mammary gland-targeted ErbB2 oncogene were crossed with c-jun(f/f) transgenic mice to determine the role of endogenous c-Jun in mammary tumor invasion and stem cell function. The excision of c-jun by Cre recombinase reduced cellular migration, invasion, and mammosphere formation of ErbB2-induced mammary tumors. Proteomic analysis identified a subset of secreted proteins (stem cell factor (SCF) and CCL5) induced by ErbB2 expression that were dependent upon endogenous c-Jun expression. SCF and CCL5 were identified as transcriptionally induced by c-Jun. CCL5 rescued the c-Jun-deficient breast tumor cellular invasion phenotype. SCF rescued the c-Jun-deficient mammosphere production. Endogenous c-Jun thus contributes to ErbB2-induced mammary tumor cell invasion and self-renewal.
Jiao
Xuanmao
X
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Katiyar
Sanjay
S
Willmarth
Nicole E
NE
Liu
Manran
M
Ma
Xiaojing
X
Flomenberg
Neal
N
Lisanti
Michael P
MP
Pestell
Richard G
RG
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D018946:Chemokine CCL5 / Q000378:metabolism; D004847:Epithelial Cells / Q000473:pathology / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics* / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D019089:Stem Cell Factor / Q000378:metabolism
D018946:Chemokine CCL5; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun; D018719:Erb-b2 Receptor Tyrosine Kinases; D019089:Stem Cell Factor; C483024:CCL5 protein, human; C000715470:MAS1 protein, human; C508053:ERBB2 protein, human