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Heregulin-Induced Activation of HER2 and HER3 Increases Androgen Receptor Transactivation and CWR-R1 Human Recurrent Prostate Cancer Cell Growth

Departments of Pathology and Laboratory Medicine, Medicine, Pediatrics, Biochemistry and Biophysics and University of North Carolina Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina

Requests for reprints: Christopher W. Gregory, Voyager Pharmaceutical Co., 8540 Colonnade Center Drive, Suite 409, Raleigh, NC 27615. Phone: 919-846-4880; Fax: 919-846-4881; E-mail: cgregory{at}voyagerpharma.com.

Purpose: 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.

Experimental Design and 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.

Key Words: androgen receptor • epidermal growth factor • tyrosine kinase inhibitor • heregulin • HER receptor tyrosine kinase

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