Androgen Receptor Controls EGFR and ERBB2 Gene Expression at Different Levels in Prostate Cancer Cell Lines

Abstract

EGFR or ERBB2 contributes to prostate cancer (PCa) progression by activating the androgen receptor (AR) in hormone-poor conditions. Here, we investigated the mechanisms by which androgens regulate EGFR and ERBB2 expression in PCa cells. In steroid-depleted medium (SDM), EGFR protein was less abundant in androgen-sensitive LNCaP than in androgen ablation-resistant 22Rv1 cells, whereas transcript levels were similar. Dihydrotestosterone (DHT) treatment increased both EGFR mRNA and protein levels and stimulated RNA polymerase II recruitment to the EGFR gene promoter, whereas it decreased ERBB2 transcript and protein levels in LNCaP cells. DHT altered neither EGFR or ERBB2 levels nor the abundance of prostate-specific antigen (PSA), TMEPA1, or TMPRSS2 mRNAs in 22Rv1 cells, which express the full-length and a shorter AR isoform deleted from the COOH-terminal domain (AR#CTD). The contribution of both AR isoforms to the expression of these genes was assessed by small interfering RNAs targeting only the full-length or both AR isoforms. Silencing of both isoforms strongly reduced PSA, TMEPA1, and TMPRSS2 transcript levels. Inhibition of both AR isoforms did not affect EGFR and ERBB2 transcript levels but decreased EGFR and increased ERBB2 protein levels. Proliferation of 22Rv1 cells in SDM was inhibited in the absence of AR and AR#CTD. A further decrease was obtained with PKI166, an EGFR/ERBB2 kinase inhibitor. Overall, we showed that AR#CTD is responsible for constitutive EGFR expression and ERBB2 repression in 22Rv1 cells and that AR#CTD and tyrosine kinase receptors are necessary for sustained 22Rv1 cell growth. [Cancer Res 2009;69(7):2941-9]

Plasma membrane-associated sialidase (NEU3) regulates progression of prostate cancer to androgen-independent growth through modulation of androgen receptor signaling

“…20 It has also been reported that the EGFR family modulates AR signaling and contributes androgenindependent tumor progression. [24][25][26][27][28] Expression levels of EGFR family were therefore evaluated as possible targets for NEU3 ( Figure 4d). NEU3 was found to increase EGFR and ERBB2 in mRNA and protein levels together with AR and PSA elevation in LNCaP cells under androgendeficient conditions, although they behaved differently in the presence of DHT.…”

Epidermal growth factor receptor expression escapes androgen regulation in prostate cancer: a potential molecular switch for tumour growth

“…It has been suggested that regulation of EGFR by androgen is disrupted in PCa (Russell et al (1998) and that 5aDHT treatment increased EGFR mRNA and protein levels in LNCaP cells (Pignon et al, 2009)). EGFR family members have a critical function in the proliferation, migration, survival, and differentiation of target cells.…”

“…Among the specific target genes that are downregulated by androgen in normal prostate tissue is the EGFR. Regulation of EGFR expression by androgens is shown to be at the transcriptional level, both in normal prostate tissue and prostate cancer (PCa) cell lines (Brass et al, 1995;Ravenna et al, 1995;Nishi et al, 1996;Itoh et al, 1998;Schwartz et al, 1998;Hammarsten et al, 2007;Pignon et al, 2009). This regulation seems to be negatively regulated in normal cells and upregulated in PCa, especially in androgen-independent PCa.…”

“…These signalling pathways may activate the AR without ligand, culminating in androgenreceptor signalling, leading to cellular proliferation, migration, and survival. The references for the reactions cited in Figure 1 are as follows: Reaction 1, Heinlein and Chang, 2004; Reaction 2, Heinlein and Chang, 2004;Reaction 3, Heinlein and Chang, 2004;Reaction 4, Heinlein and Chang, 2004;Reaction 5, Heinlein and Chang, 2004;Reaction 6, Heinlein and Chang, 2004;Reaction 7, Brass et al, 1995;Ravenna et al, 1995;Itoh et al, 1998;Schwartz et al, 1998;Heinlein and Chang, 2004;Hammarsten et al, 2007;Pignon et al, 2009;Reaction 8, Nishi et al, 1996;Reaction 9, Traish and Wotiz, 1987;St-Arnaud et al, 1988;Reaction 10, Sugita et al, 2004;Gregory et al, 2005;Migliaccio et al, 2006;Léotoing et al, 2007;Zhu and Kyprianou, 2008;Recchia et al, 2009;Reaction 11, Migliaccio et al, 2006;Léotoing et al, 2007;Zhu and Kyprianou, 2008;Recchia et al, 2009;Reaction 12, Migliaccio et al, 2006;Léotoing et al, 2007;Zhu and Kyprianou, 2008;Recchia et al, 2009;Reaction 13, Migliaccio et al, 2006;Léotoing et al, 2007;Zhu and Kyprianou, 2008;Recchia et al, 2009;Reaction 14, Migliaccio et al, 2006;Léotoing et al, 2007;Zhu and Kyprianou, 2008;Recchia et al, 2009. Abbreviations: AKT, protein kinase B; AR, androgen receptor; ARE, androgen response element; 5a-DHT, d...…”

Radiotherapy and inhibition of the EGF family as treatment strategies for prostate cancer: combining theragnostics with theragates

“…Studies have shown that EGF kinase signals are mandatory for optimal AR functioning at low androgen concentrations and that these signals are not mediated through EGFR, but rather through the association of HER2 with other members of the EGF receptor family. Thus, overexpression of HER2 may enhance AR function and consequently also promote androgen resistant growth [25,26]. Recently, Jain et al [27] also demonstrated that EGFR kinase inhibition caused oncogenic switch to HER2 signaling in a preclinical study.…”