Epidermal growth factor receptor-dependent stimulation of amphiregulin expression in androgen-stimulated human prostate cancer cells.

Abstract

Amphiregulin is a heparin-binding epidermal growth factor (EGF)-related peptide that binds to the EGF receptor (EGF-R) with high affinity. In this study, we report a role for amphiregulin in androgen-stimulated regulation of prostate cancer cell growth. Androgen is known to enhance EGF-R expression in the androgen-sensitive LNCaP human prostate carcinoma cell line, and it has been suggested that androgenic stimuli may regulate proliferation, in part, through autocrine mechanisms involving the EGF-R. In this study, we demonstrate that LNCaP cells express amphiregulin mRNA and peptide and that this expression is elevated by androgenic stimulation. We also show that ligand-dependent EGF-R stimulation induces amphiregulin expression and that androgenic effects on amphiregulin synthesis are mediated through this EGF-R pathway. Parallel studies using the estrogen-responsive breast carcinoma cell line, MCF-7, suggest that regulation of amphiregulin by estrogen may also be mediated via an EGF-R pathway. In addition, heparin treatment of LNCaP cells inhibits androgen-stimulated cell growth further suggesting that amphiregulin can mediate androgen-stimulated LNCaP proliferation. Together, these results implicate an androgen-regulated autocrine loop composed of amphiregulin and its receptor in prostate cancer cell growth and suggest that the mechanism of steroid hormone regulation of amphiregulin synthesis may occur through androgen upregulation of the EGF-R and subsequent receptor-dependent pathways.

5α-Androstane-3α,17β-diol activates pathway that resembles the epidermal growth factor responsive pathways in stimulating human prostate cancer LNCaP cell proliferation

“…It has been reported that 5a-DHT does not change intracellular levels of EGF. 44 Although upregulation in EGFR has been detected when these cells were cultured in the presence of androgens, 45,46 it has been shown that 5a-DHT-stimulated LNCaP cell proliferation is not inhibited by the addition of anti-EGFR neutralizing monoclonal. This suggests that autocrine activation of EGFR is absent in androgen stimulation.…”

Differential regulation of cell proliferation and protease secretion by epidermal growth factor and amphiregulin in tumoral versus normal breast epithelial cells

“…These data reveal differential behaviour of normal versus tumoral breast epithelial cells in regard to the action of AR and demonstrate that, in a number of cases, AR might play a significant role in tumour progression through the regulation of the PA/plasmin system. Whereas the expression of AR in a variety of both nontransformed and tumoral cells appears to be stimulated in the presence of EGF (Normanno et al, 1994b;Sehgal et al, 1994), the potential regulation of AR by growth factors in normal breast epithelial cells has never been examined. Because previous studies suggest that dysregulated expression of AR may be a component of mammary tumorigenesis we proposed to analyse and to compare the regulation of amphiregulin gene expression and protein secretion by EGF in normal and tumoral breast epithelial cells.…”

“…AR is expressed in several tissues, such as human ovary, placenta, lung, kidney, stomach, colon and breast (Johnson et al, 1992;Lejeune et al, 1993). Increased evidences strongly suggest that AR may function as a potential autocrine growth factor in tumoral as well as in their counterpart normal cells, such as prostatic (Sehgal et al, 1994), colonic (Johnson et al, 1992;Normanno et al, 1995), and mammary epithelial cells (Li et al, 1992;Normanno et al, 1994a, b). Moreover, overexpression of AR has been detected in several oestrogen-responsive and -unresponsive breast cancer cell lines as well as in approximately 80% of human primary breast carcinoma (Martinez-Lacaci et al, 1995;Visscher et al, 1997).…”

A Differential Requirement for the COOH-terminal Region of the Epidermal Growth Factor (EGF) Receptor in Amphiregulin and EGF Mitogenic Signaling

“…AR is commonly overexpressed in human malignancies of the colon (22,28), stomach (29 -31), breast (32), and in the pancreas, overexpression correlates with reduced patient survival (26,33). In vitro, AR has been shown to function in an autocrine manner to drive the proliferation of malignant cells of the colon (22), breast (24), cervix (34), prostate (35), and pancreas (26,27).…”