ETV6-NTRK3 fusion oncogene initiates breast cancer from committed mammary progenitors via activation of AP1 complex.
To better understand the cellular origin of breast cancer, we developed a mouse model that recapitulates expression of the ETV6-NTRK3 (EN) fusion oncoprotein, the product of the t(12;15)(p13;q25) translocation characteristic of human secretory breast carcinoma. Activation of EN expression in mammary tissues by Wap-Cre leads to fully penetrant, multifocal malignant breast cancer with short latency. We provide genetic evidence that, in nulliparous Wap-Cre;EN females, committed alveolar bipotent or CD61(+) luminal progenitors are targets of tumorigenesis. Furthermore, EN transforms these otherwise transient progenitors through activation of the AP1 complex. Given the increasing relevance of chromosomal translocations in epithelial cancers, such mice serve as a paradigm for the study of their genetic pathogenesis and cellular origins, and generation of preclinical models.
Li
Zhe
Z
Division of Hematology/Oncology, Children's Hospital Boston, Boston, MA 02115, USA.
Tognon
Cristina E
CE
Godinho
Frank J
FJ
Yasaitis
Laura
L
Hock
Hanno
H
Herschkowitz
Jason I
JI
Lannon
Chris L
CL
Cho
Eunah
E
Kim
Seong-Jin
SJ
Bronson
Roderick T
RT
Perou
Charles M
CM
Sorensen
Poul H
PH
Orkin
Stuart H
SH
D000483:Alleles; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D051927:CD24 Antigen / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D019426:Integrases / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000473:pathology*; D015674:Mammary Neoplasms, Animal / Q000473:pathology; D051379:Mice; D005810:Multigene Family; D014411:Neoplastic Stem Cells / Q000473:pathology*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D010298:Parity; D019683:Penetrance; D011247:Pregnancy; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D000097764:ETS Translocation Variant 6 Protein; D020812:Receptor, trkC
D051927:CD24 Antigen; D019426:Integrases; D015514:Oncogene Proteins, Fusion; D050783:Proto-Oncogene Proteins c-ets; D016755:Proto-Oncogene Proteins c-jun; D012097:Repressor Proteins; D018808:Transcription Factor AP-1; D000097764:ETS Translocation Variant 6 Protein; C526167:ETV6-NTRK3 fusion protein, mouse; D020812:Receptor, trkC; C045073:Cre recombinase