Heregulin-induced activation of HER2 and HER3 increases androgen receptor transactivation and CWR-R1 human recurrent prostate cancer cell growth.
OBJECTIVE
The androgen receptor (AR) is a ligand-dependent transcription factor that mediates gene expression and growth of normal and malignant prostate cells. In prostate tumors that recur after androgen withdrawal, the AR is highly expressed and transcriptionally active in the absence of testicular androgens. In these "androgen-independent" tumors, alternative means of AR activation have been invoked, including regulation by growth factors and their receptors in prostate cancer recurrence.


RESULTS
In this report, we show that HER receptor tyrosine kinases 1 through 4 are expressed in the CWR-R1 recurrent prostate cancer cell line; their stimulation by epidermal growth factor (EGF) and heregulin activates downstream signaling, including mitogen-activated protein kinase and phosphatidylinositol-3 kinase and Akt pathways. We show that heregulin activates HER2 and HER3 and increases androgen-dependent AR transactivation of reporter genes in CWR-R1 cells. Tyrosine phosphorylation of HER2 and HER3, AR transactivation, and cell proliferation induced by heregulin were more potently inhibited by the EGFR/HER2 dual tyrosine kinase inhibitor GW572016 (lapatinib) than the EGFR-specific inhibitor ZD1839 (gefitinib). Basal proliferation in the absence of growth factors was also inhibited by GW572016 to a greater extent than ZD1839, suggesting that low level HER2/HER3 activation perhaps by an autocrine pathway contributes to the proliferation signal.


CONCLUSIONS
These data indicate that heregulin signaling through HER2 and HER3 increases AR transactivation and alters growth in a recurrent prostate cancer cell line. Therefore, inhibition of low-level HER2 signaling may be a potential novel therapeutic strategy in prostate cancer.
Gregory
Christopher W
CW
Department of Pathology and Laboratory Medicine, University of North Carolina Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
Whang
Young E
YE
McCall
Wesley
W
Fei
Xiaoyin
X
Liu
Yuanbo
Y
Ponguta
Liliana A
LA
French
Frank S
FS
Wilson
Elizabeth M
EM
Earp
H Shelton
HS
D017930:Genes, Reporter; D018734:Genes, erbB-2; D006801:Humans; D008297:Male; D020890:Neuregulin-1 / Q000494:pharmacology*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000473:pathology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D020893:Receptor, ErbB-3 / Q000096:biosynthesis*; D011944:Receptors, Androgen / Q000096:biosynthesis* / Q000235:genetics; D012008:Recurrence; D015398:Signal Transduction; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D011944:Receptors, Androgen; D014443:Tyrosine