Constitutive Tyrosine Phosphorylation of ErbB-2 via Jak2 by Autocrine Secretion of Prolactin in Human Breast Cancer

Abstract

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.

Regulation of bcl-2 gene expression in human breast cancer cells by prolactin and its antagonist, hPRL-G129R

“…The cell lines used in the cDNA subtraction experiments have been reported to produce PRL as an autocrine/paracrine growth factor, from the work of others (Ginsburg and Vonderhaar, 1995;Shaw-Bruha et al, 1997;Yamauchi et al, 2000). We do not have evidence, at this point, that hPRL-G129R contains an intrinsic ability to elicit novel signal transduction of its own.…”

Bacterial N-acylhomoserine lactone-induced apoptosis in breast carcinoma cells correlated with down-modulation of STAT3

“…Both proteins, either directly or through Gab1, transmit signals to the ERK cascade (Hirano et al, 2000;Yamauchi et al, 2000). Activation of this hypothetical pathway would be consistent with IEG expression and autocrine secretion, which are implicated as downstream events in the pathway blocked by OdDHL (Li and Shaw, 2002 and unpublished data).…”

Prolactin modulates phosphorylation, signaling and trafficking of epidermal growth factor receptor in human T47D breast cancer cells

“…It is increasingly appreciated that interactions and crosstalk among signaling pathways allow both integration and diversity in responses to cellular stimuli. EGFR and cytokine receptor family member signaling pathways can interrelate in various ways (Johnson et al, 1996;Fenton and Sheffield, 1997;Wiepz et al, 1997;Yamauchi et al, 1997Yamauchi et al, , 1998Yamauchi et al, , 2000Qiu et al, 1998;Quijano and Sheffield, 1998;Kim et al, 1999;Maus et al, 1999;Badache and Hynes, 2001;Huang et al, 2003;Eisenberg et al, 2004). We previously focused on interactions between GH/GHR signaling and signaling mediated by intrinsic tyrosine kinase growth factor receptors, including EGFR and ErbB-2, in murine preadipocytes (Kim et al, 1999;Huang et al, 2003Huang et al, , 2004a.…”

“…Recent studies suggest that PRL, growth hormone (GH) and other cytokines may use multiple mechanisms to crosstalk with EGFR and/or ErbB-2 (Johnson et al, 1996;Fenton and Sheffield, 1997;Wiepz et al, 1997;Yamauchi et al, 1997Yamauchi et al, , 1998Yamauchi et al, , 2000Qiu et al, 1998;Quijano and Sheffield, 1998;Kim et al, 1999;Maus et al, 1999;Badache and Hynes, 2001;Huang et al, 2003). For example, GH causes EGFR tyrosine phosphorylation without the activation of EGFR kinase activity (Yamauchi et al, 1997;Kim et al, 1999).…”