Cross-Talk between Estrogen Receptor and Growth Factor Pathways as a Molecular Target for Overcoming Endocrine Resistance

Abstract

Introduced more than 100 years ago, endocrine therapy is still the most important systemic therapy for all stages of estrogen receptor (ER) -positive breast tumors. A major clinical problem limiting the usefulness of this therapy is tumor resistance, either de novo or acquired during the course of the treatment. Relatively new discoveries emphasize the complexity of ER signaling and its multiple regulatory interactions with growth factor and other kinase signaling pathways. Both genomic (nuclear) and nongenomic (membrane and cytoplasmic) ER activities contribute to this intimate cross-talk, which is probably a fundamental factor in endocrine resistance. New targeted therapies, especially against the epidermal growth factor receptor/HER-2 pathway, should be carefully evaluated in more (bio)logical strategies to enable them to be exploited appropriately. A strategy of combining endocrine therapy (particularly tamoxifen) with these inhibitors, to circumvent de novo and acquired resistance, will be discussed. We will also emphasize open questions and future challenges in the dynamic research field of molecular ER biology from the endocrine therapy perspective.

Loss of protein tyrosine phosphatase, non-receptor type 2 is associated with activation of AKT and tamoxifen resistance in breast cancer

“…Alterations in the PI3K/AKT pathway, mainly PIK3CA mutations, have been shown most frequent in the luminal subtypes, suggesting a crosstalk between ER and PI3K/AKT [3]. Aberrant PI3K/AKT signalling has been connected to poor response to anti-oestrogen therapies in several studies [20,[42][43][44][45][46][47][48][49][50]. In the present study, we showed PTPN2 gene loss as a new potential marker of endocrine resistance.…”

17β-Hydroxysteroid dehydrogenases involved in local oestrogen synthesis have prognostic significance in breast cancer

“…This could indicate that tamoxifen does not completely block the action of E2 in some patients due to high levels of E2. Acquired tamoxifen resistance is believed to arise due to increased phosphorylation of the ER by growth factor signalling or due to increased expression of coactivators (Nicholson et al, 2004, Schiff et al, 2004. This means that tamoxifen acts as an agonist after long duration of treatment in some patients, and the question is how the resistant tumour cells will respond to high E2 levels after the completion of tamoxifen treatment.…”

Transcriptional regulation prediction of antiestrogen resistance in breast cancer based on RNA polymerase II binding data

“…In addition, non-genomic action of estrogen often includes ligand binding to the ER at the plasma membrane and follows the activation of signaling pathways. It has been demonstrated that several signaling kinases interacted with and were activated by the ER, including IGF-1R (insulin-like growth factor-1 receptor), Src, PI3K (phosphatidylinositol 3-kinase), MAPK (mitogen-activated protein kinase), protein kinases A and C and calcium pathways [65], EGFR (epidermal growth factor receptor) and ErbB-2, with non-genomic effects of the ER [66,67]. Furthermore, genomic and non-genomic mechanisms of action of ER are not mutually exclusive, but many interactions exist between these two modes [4].…”