Resistance to endocrine therapy in breast cancer: exploiting estrogen receptor/growth factor signaling crosstalk

Abstract

Targeting the estrogen receptor (ER) is the oldest form of molecular targeted therapy, and the widespread use of the selective estrogen receptor modulator tamoxifen in breast cancer is responsible for major improvements in cure rates, quality of life, and disease prevention in the last 25 years. Newer forms of endocrine therapy now available for the management of endocrine responsive breast cancer include a new generation of aromatase inhibitors, which lower the estrogen ligand for ER, and pure ER antagonists which destroy the receptor. Despite these recent clinical advances, intrinsic and acquired resistance to these endocrine therapies is still a common feature that limits the success of this therapeutic strategy. Recent research into the molecular biology of ER signaling has revealed a remarkably complex interactive signaling with other growth factor signaling pathways in breast cancer cells, potentially explaining some of the reasons behind endocrine therapy action as well as resistance. This view of a more complex ER signaling system has uncovered new molecular targets which, if present in a cancer cell, might be additionally targeted using various signal transduction inhibitors to overcome or prevent resistance to endocrine therapy. In addition, the dynamic inverse relationship between the expression of ER and growth factor receptors brings more excitement to the potential of restoring ER expression in apparently ER-negative cells by inhibition of growth factor signaling. Ongoing clinical trials of endocrine therapy combined with growth factor pathway inhibitors or their downstream signaling elements promise to further improve the present care for breast cancer patients.

Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma

“…to the development of either de novo or acquired antiestrogen resistance (Massarweh and Schiff, 2006;Arpino et al, 2008). Elevated expression of epidermal growth factor receptor (EGFR) and HER2 and activation of downstream signaling molecules such as p42/44 MAPK and phosphatidylinositol 3-kinase (PI3K)/AKT have been shown in antiestrogen-resistant cell lines and tumors (McClelland et al, 2001;Knowlden et al, 2003;Massarweh et al, 2008).…”

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

“…On the basis of these studies, several clinical trials have attempted to overcome resistance through combination with growth factor signaling inhibitors Massarweh and Schiff, 2006). However, results of these trials are relatively insufficient and, therefore, deeper knowledge of the mechanism of acquired resistance is needed.…”

E-cadherin mediates the aggregation of breast cancer cells induced by tamoxifen and epidermal growth factor

“…Nearly 70% of breast tumors express the ERα which allows for the use of antiestrogen therapy as a reliable therapeutic approach for all stages of the disease [42]. The ER antagonist tamoxifen has been shown to improve survival in early breast cancer [43] as well as the quality of life in patients with metastatic disease [13].…”

“…Furthermore, almost all patients with metastatic disease and many who receive tamoxifen as adjuvant therapy eventually experience tumor relapse (acquired resistance). Thus, tamoxifen resistance occurs frequently in breast cancer patients and seriously limits treatment efficacy [42,44]. Multiple mechanisms have been proposed to contribute to the failure of tamoxifen therapy, including changes in the uptake or metabolism of tamoxifen, presence of ER mutants and ligand-independent ER activation, loss of expression of ER and/or cofactors and modification of the estrogen response element [42,45].…”

“…A large body of clinical and experimental studies has suggested that alteration of ER function by growth factor pathways may be involved in tamoxifen resistance [14,42,[46][47][48]. In this context, it has been reported that phosphorylation of ERα by EGFR-mediated signaling enhances the estrogeninduced transcriptional activity [49,50].…”