Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer

Abstract

Tamoxifen has been the mainstay of hormonal therapy in both early and advanced breast cancer patients for approximately three decades. The availability of novel compounds such as aromatase inhibitors (AIs) and fulvestrant, with different mechanism of action, is changing the scenario of endocrine treatment of postmenopausal breast cancer patients. In this review article, we have summarized the current knowledge of the mechanisms of resistance to endocrine therapy, in order to derive information that might be useful for therapeutic intervention. We propose that resistance to endocrine therapy is a progressive, step-wise phenomenon induced by the selective pressure of hormonal agents, which leads breast cancer cells from an estrogen-dependent, responsive to endocrine manipulation phenotype to a non-responsive phenotype, and eventually to an estrogenindependent phenotype. In particular, evidence suggests for each 'action' introduced to block estrogen stimulation of breast cancer cells (i.e. treatment with anti-estrogen), there are one or more corresponding 'reactions' that tumor cells can use to escape our attempts to block their growth: estrogen hypersensitivity associated with increased transcriptional activity of estrogen receptor a (ERa) and/or increased non-genomic activity of ERa, estrogen supersensitivity, increased growth factor signaling, suppression of ERa expression and finally estrogen independence. Activation of growth factor signaling is involved in each step of this phenomenon, and might ultimately substitute estrogen in sustaining the growth and the survival of breast cancer cells. In this respect, results of pre-clinical and clinical studies with AIs, fulvestrant and signaling inhibitors sustain this hypothesis. More importantly, the knowledge of the mechanisms involved in the resistance of breast cancer cells to endocrine therapy offers potential for novel therapeutic strategies.

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

“…Current literature supports the hypothesis that acquired resistance is mainly mediated by molecular events that-particularly in the case of resistance to AIs-lead to constitutive activation of ERa and growth factor signaling pathway cross-talk (Clarke et al, 2003;Martin et al, 2003;Yue et al, 2003;Jelovac et al, 2005;Normanno et al, 2005;Sabnis et al, 2005;Santen et al, 2005;Masri et al, 2008). 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).…”

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

“…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]. …”

“…The genomic action mode mediates genomic transcription regulation through nuclear-initiated steroid signaling, and the non-genomic mode activates various protein kinase cascades [4]. Both the genomic and non-genomic pathways play a role in the response to estrogen signaling and are regulated by TFs in breast cancer cells.…”

“…Both the genomic and non-genomic pathways play a role in the response to estrogen signaling and are regulated by TFs in breast cancer cells. Furthermore, the genomic and non-genomic mechanisms of action of the ER are not mutually exclusive, but many interactions exist between these two modes [4]. Previous studies about endocrine resistance in breast cancer have shown that TAM-resistant sublines (OHT) often show changes at the level of transcriptional regulation compared with wild-type breast cancer (MCF7) cells [12].…”

A Review of Chromatographic Methods Used in the Determination of Anastrozole Levels

“…However, its long term use is limited by life-threatening adverse effects [6][7][8][9] , and some patients can become resistant [10,11] . As a result of these challenges, three AIs including ANA were introduced to either serve as TAM alternatives or to be used following several years of TAM therapy [4,10,[12][13][14] .…”