A Naturally Occurring HER2 Carboxy-Terminal Fragment Promotes Mammary Tumor Growth and Metastasis

Abstract

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.HER2 (ErbB2) is a type I transmembrane protein that belongs to the epidermal growth factor receptor (EGFR, ErbB1, HER1) family. Two additional members, HER3 and -4 (ErbB3 and -4), complete this family. When an EGF-like ligand binds to HER1, -3, or -4, its extracellular domain adopts the socalled open conformation, which allows the formation of homo-or heterodimers (5). Despite not binding any ligand, HER2 readily interacts with other ligand-bound HER receptors because its extracellular domain is constitutively in an open conformation (10).At the cell surface, dimerization of the extracellular domains leads to interaction between the intracellular kinases of the HER receptors and subsequent transphosphorylation of tyrosine residues in the C-terminal tails. The phosphotyrosines act as docking sites for proteins that initiate signals which are transduced to the nucleus through different pathways, including the mitogen-activated protein kinases (MAPKs), phosphoinositide-3-kinase-activated Akt, Src, and phospholipase C gamma (PLCgamma) pathways. These signaling circuitries control the expression of target genes that act coordinately to modify key aspects of cellular biology, including proliferation, migration, survival, and differentiation (7).In addition to the canonical mode, HER receptors or fragments of them are capable of direct signaling. For example, a nuclear carboxy-terminal fragment (CTF) encompassing the entire cytoplasmic domain of HER4 has been shown to regulate gene transcription (22,39). The CTF of HER4 is generated at the plasma membrane by the sequential action of two types of proteolytic enzymes known as the alpha-and gammasecretases. Alpha-secre...

ADAM17 (TACE) regulates TGFβ signaling through the cleavage of vasorin

“…Then media were harvested and cells lysed as described in the study by Pedersen et al (2009). Glycoproteins from the conditioned media and from the clarified cell lysates were purified with agglutinin (wheat germ agglutinin) chromatography, loaded into 10% SDS-polyacrylamide gel, transferred to nitrocellulose membranes and blotted with anti-VASN antibody.…”

Modulation of HER2 Tyrosine/Threonine Phosphorylation and Cell Signalling

“…This may provide further evidence of specific enzymatic digestion of HER2 into novel biologic agents [44,45]. The low molecular weight of this identified fragment and its association with the membrane fraction raises the possibility that it may function as a ligand for another, as yet unidentified, receptor.…”

Prognostic value of expression of intracellular and extracellular domains of HER2 in patients with HER2-possitive breast cancer

“…It is possible thanks to internal ribosome entry sites (IRES) present in the HER2 transcript as codons for methionine 611 and 687. These alternative protein products are also known as carboxyl-terminal fragments (CTF) [31][32][33][34]. P95 expression is regarded as a marker of poor prognosis and a negative predictive factor for trastuzumab treatment in patients with HER2-positive breast cancer [34].…”