Estrogen suppression of EGFR expression in breast cancer cells: A possible mechanism to modulate growth

Abstract

Epidermal growth factor receptor (EGFR) is a transmembrane receptor whose overexpression in breast cancer predicts for poor prognosis and is inversely correlated with expression of estrogen receptor (ER). This study was designed to investigate whether estrogen plays an active role in suppression of EGFR expression in estrogen-responsive breast cancer cell lines expressing low levels of EGFR. Upon withdrawal of estrogen, EGFR mRNA and protein increased 3±6 fold in MCF-7, T47D, and BT474 ER breast cancer cells. This was reversible upon addition of estradiol back to the culture media, but only after prolonged treatment. Nuclear run-on assays and studies with the transcription inhibitor actinomycin D demonstrated that regulation is at the transcriptional level. These results indicate that in the presence of estrogen, ER breast cancer cells possess active mechanisms to suppress EGFR expression. Up-regulation of EGFR in response to estrogen depletion and growth inhibition could represent an attempt to rescue cell growth by utilizing an alternative pathway. Indeed, we found that estrogen-depleted breast cancer cells are more sensitive to the mitogenic effects of EGF and TGF-a, and simultaneous blockade of both estrogen and EGFR signaling pathways induced cell death.

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

“…Inhibition of ER expression or oestradiol deprivation or treatment with anti-oestrogen increased EGFR expression in breast cancer cell lines, suggesting a complex control mechanism (Lichtner, 2003;Osborne et al, 2005) An oestrogen-independent growth ensues through alternative mechanisms during oestrogen deprivation or anti-oestrogen treatment. Upregulation of EGFR in response to oestrogen depletion was considered to be one of the survival mechanisms of tumour cells (Yarden et al, 2001). Thus, in ER-positive breast cancer cells, oestrogen is actively involved in the suppression of EGFR expression, whereas in ER-negative tumours, EGFR expression is increased.…”

Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells

“…EGFR and Jak2 tyrosine kinases induce activation of Stat3 and expression of Bcl-2 in metastatic 435 cells EGFR has been shown to increase the tumorigenic potential of transformed human mammary epithelial cells (Ma et al, 1998), and its overexpression in breast cancer predicts for poor prognosis and is inversely correlated with expression of ER (Yarden et al, 2001). Here, we analysed whether inhibition of the EGFR tyrosine kinase activity was able to down-regulate both activation of Stat3 and expression of Bcl-2 in metastatic breast cancer cells.…”

Endocrine Resistance and Epithelial Mesenchymal Transition in Breast Cancer

“…MAPK/ERK, PI3K/AKT, p90RSK and p38 MAPK pathways can specifically activate ER at key positions (serine 118 and 167 and threonine 311) in the AF-1 domain and in other domains (Bunone et al, 1996;Campbell et al, 2001;Joel et al, 1998;Kato et al, 1995). Expression of ligands and receptors such as transforming growth factor-(TGF ), IGF1 and IGF1R can be increased by estrogen and those can then initiate signalling while expression of other receptors such as EGFR and ERBB2 is decreased by estrogen signaling (Kushner et al, 2000;Massarweh et al, 2008;Umayahara et al, 1994;Vyhlidal et al, 2000;Yarden et al, 2001). In addition, activation of the PI3K/AKT and the p42/44 MAPK pathways by these receptors down-regulates the expression of ER and PR causing reduction in estrogen dependency while activating the transcriptional function of ER, which suggests a contribution of this cross talk to the relative resistance to endocrine therapies in tumours with amplified ERBB2 expression (Bayliss et al, 2007;Brinkman and El-Ashry, 2009;Creighton et al, 2010;Lopez-Tarruella and Schiff, 2007).…”