A naturally occurring HER2 carboxy-terminal fragment promotes mammary tumor growth and metastasis.
HER2 is a tyrosine kinase receptor causally involved in cancer. A subgroup of breast cancer patients with particularly poor clinical outcomes expresses a heterogeneous collection of HER2 carboxy-terminal fragments (CTFs). However, since the CTFs lack the extracellular domain that drives dimerization and subsequent activation of full-length HER2, they are in principle expected to be inactive. Here we show that at low expression levels one of these fragments, 611-CTF, activated multiple signaling pathways because of its unanticipated ability to constitutively homodimerize. A transcriptomic analysis revealed that 611-CTF specifically controlled the expression of genes that we found to be correlated with poor prognosis in breast cancer. Among the 611-CTF-regulated genes were several that have previously been linked to metastasis, including those for MET, EPHA2, matrix metalloproteinase 1, interleukin 11, angiopoietin-like 4, and different integrins. It is thought that transgenic mice overexpressing HER2 in the mammary glands develop tumors only after acquisition of activating mutations in the transgene. In contrast, we show that expression of 611-CTF led to development of aggressive and invasive mammary tumors without the need for mutations. These results demonstrate that 611-CTF is a potent oncogene capable of promoting mammary tumor progression and metastasis.
Medical Oncology Research Program, Vall d'Hebron University Hospital, Psg. Vall d'Hebron 119-129, 08035 Barcelona, Spain.
Kim
K
Pedersen
Pier-Davide
PD
Angelini
Sirle
S
Laos
Alba
A
Bach-Faig
Matthew P
MP
Cunningham
Cristina
C
Ferrer-Ramón
Antonio
A
Luque-García
Jesús
J
García-Castillo
Josep Lluis
JL
Parra-Palau
Maurizio
M
Scaltriti
Santiago
S
Ramón y Cajal
José
J
Baselga
Joaquín
J
Arribas
D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000556:secondary; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000209:etiology / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008969:Molecular Sequence Data; D010442:Peptide Chain Initiation, Translational; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection
D010446:Peptide Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human