Constitutive tyrosine phosphorylation of ErbB-2 via Jak2 by autocrine secretion of prolactin in human breast cancer.
Overexpression of the oncogene for ErbB-2 is an unfavorable prognostic marker in human breast cancer. Its oncogenic potential appears to depend on the state of tyrosine phosphorylation. However, the mechanisms by which ErbB-2 is constitutively tyrosine-phosphorylated in human breast cancer are poorly understood. We now show that human breast carcinoma samples with ErbB-2 overexpression have higher proliferative and metastatic activity in the presence of autocrine secretion of prolactin (PRL). By using a neutralizing antibody or dominant negative (DN) strategies or specific inhibitors, we also show that activation of Janus kinase Jak2 by autocrine secretion of PRL is one of the significant components of constitutive tyrosine phosphorylation of ErbB-2, its association with Grb2 and activation of mitogen-activated protein (MAP) kinase in human breast cancer cell lines that overexpress ErbB-2. Furthermore, the neutralizing anti-PRL antibody or erbB-2 antisense oligonucleotide or DN Jak2 or Jak2 inhibitor or DNRas or MAP kinase kinase inhibitor inhibits the proliferation of both untreated and PRL-treated cells. Our results indicate that autocrine secretion of PRL stimulates tyrosine phosphorylation of ErbB-2 by Jak2, provides docking sites for Grb2 and stimulates Ras-MAP kinase cascade, thereby causing unrestricted cellular proliferation. The identification of this novel cross-talk between ErbB-2 and the autocrine growth stimulatory loop for PRL may provide new targets for therapeutic and preventive intervention of human breast cancer.
Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113, Japan.
T
T
Yamauchi
N
N
Yamauchi
K
K
Ueki
T
T
Sugiyama
H
H
Waki
H
H
Miki
K
K
Tobe
S
S
Matsuda
T
T
Tsushima
T
T
Yamamoto
T
T
Fujita
Y
Y
Taketani
M
M
Fukayama
S
S
Kimura
Y
Y
Yazaki
R
R
Nagai
T
T
Kadowaki
D048868:Adaptor Proteins, Signal Transducing; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D002455:Cell Division; D005260:Female; D051380:GRB2 Adaptor Protein; D006801:Humans; D053614:Janus Kinase 2; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D011388:Prolactin / Q000378:metabolism / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011506:Proteins / Q000502:physiology; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D053614:Janus Kinase 2; D020928:Mitogen-Activated Protein Kinases; D011388:Prolactin; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D014443:Tyrosine; C495948:GRB2 protein, human; C507924:JAK2 protein, human