Pathways to tamoxifen resistance

Abstract

Therapies that target the synthesis of estrogen or the function of estrogen receptor(s) have been developed to treat breast cancer. While these approaches have proven to be beneficial to a large number of patients, both de novo and acquired resistance to these drugs is a significant problem. Recent advances in our understanding of the molecular mechanisms that contribute to resistance have provided a means to begin to predict patient responses to these drugs and develop rational approaches for combining therapeutic agents to circumvent or desensitize the resistant phenotype. Here, we review common mechanisms of antiestrogen resistance and discuss the implications for prediction of response and design of effective combinatorial treatments.

Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma

“…Although the mechanisms by which growth factor signaling pathways promote antiestrogen resistance have not been fully determined, cumulative experimental data suggest that activated growth factor signaling cross-talks with ER signaling resulting in ligandindependent or tamoxifen-induced ER activation with consequent promotion of tamoxifen-resistant tumor cell growth (Riggins et al, 2007;Arpino et al, 2008). Our data also supported a potential functional interaction between ARTN and ER signaling through which ER activation upregulates ARTN expression and ARTN stimulation increases ER activity.…”

The substrate domain of BCAR1 is essential for anti-estrogen-resistant proliferation of human breast cancer cells

“…How BCAR1 achieved tamoxifen-resistant tumor cell proliferation was not clear from our previous work, but was anticipated to involve SRC-BCAR1 complexes [7,20,23,24]. SRC was shown to bind to the Src-binding site and to phosphorylate several YXXP motifs of BCAR1 [30][31][32][33].…”

“…However, in most patients with advanced disease, the available endocrine treatments ultimately fail due to the development of therapy resistance. Despite the detailed insights in ER function, the mechanism of this general therapy failure is still poorly understood [3][4][5][6][7].…”

“…These domains are mostly conserved among the family members NEDD9 (HEF1/Cas-L), EFS (Sin) and HEPL [21]. As a consequence of the multiple protein interaction sites, BCAR1 serves as a docking molecule and has been implicated in many cellular processes, including cell transformation, integrin signaling, estrogen signaling, cell death, cytoskeletal rearrangements, migration, proliferation, force sensing, and bacterial infection [7,12,19,20,[22][23][24][25]. The closely related family member NEDD9/HEF1/CAS-L (hereafter referred to as HEF1) is unable to substitute for BCAR1 in vivo, since p130Cas knock-out mice die in utero due to developmental cardiovascular defects and growth retardation [26].…”

“…SRC was shown to bind to the Src-binding site and to phosphorylate several YXXP motifs of BCAR1 [30][31][32][33]. These experiments have shown that BCAR1 phosphorylation may be important for some processes (cell migration), but not essential for anchorage-independent growth of SRC transformed fibroblasts [7,23,24,[34][35][36]. Another important finding was the functional association between the C-terminal ends of BCAR1 and BCAR3 (AND-34) [37][38][39][40][41], the latter also identified in our functional screen for tamoxifen resistance [42].…”