Mechanisms of acquired resistance to endocrine therapy in hormone-dependent breast cancer cells

Abstract

Acquired resistance is a major problem limiting the clinical benefit of endocrine therapy. To investigate the mechanisms involved, two in vitro models were developed from MCF-7 cells. Long-term culture of MCF-7 cells in estrogen deprived medium (LTED) mimics aromatase inhibition in patients. Continued exposure of MCF-7 to tamoxifen represents a model of acquired resistance to antiestrogens (TAM-R). Long-term estrogen deprivation results in sustained activation of the ERK MAP kinase and the PI3 kinase/mTOR pathways. Using a novel Ras inhibitor, farnesylthiosalicylic acid (FTS), to achieve dual inhibition of the pathways, we found that the mTOR pathway plays the primary role in mediation of proliferation of LTED cells. In contrast to the LTED model, there is no sustained activation of ERK MAPK but enhanced responsiveness to rapid stimulation induced by E(2) and TAM in TAM-R cells. An increased amount of ERalpha formed complexes with EGFR and c-Src in TAM-R cells, which apparently resulted from extra-nuclear redistribution of ERalpha. Blockade of c-Src activity drove ERalpha back to the nucleus and reduced ERalpha-EGFR interaction. Prolonged blockade of c-Src activity restored sensitivity of TAM-R cells to tamoxifen. Our results suggest that different mechanisms are involved in acquired endocrine resistance and the necessity for individualized treatment of recurrent diseases.

Targeting of the adaptor protein Tab2 as a novel approach to revert tamoxifen resistance in breast cancer cells

“…Other TamR sublines derived in our laboratories were shown to have constitutive activation of Akt (Frogne et al, 2005) and increased level of PKCd (Nabha et al, 2005) and PKCa (Frankel et al, 2007). Other groups have reported that activation of several growth factor receptor pathways, including ERBB2, EGFR and PKA can lead to Tam resistance (Shou et al, 2004;Yue et al, 2007;Pancholi et al, 2008). Interestingly, we could demonstrate Tab2-dependency also in BT474 cells, which carry amplified HER2.…”

“…Among the mechanisms proposed to explain primary and acquired Tam resistance in breast cancer cells that maintain expression of ERa, there are constitutive activation of components of signaling pathways stemming from membrane growth factor receptors, resulting in re-distribution of coactivators or corepressors (Privalsky, 2004;Frogne et al, 2005;Schiff et al, 2005;Frankel et al, 2007;Yue et al, 2007;Pancholi et al, 2008;Musgrove and Sutherland, 2009). In addition, it was shown that the coactivator SRC3/AIB1, which is often amplified and overexpressed in breast cancer, induced Tam resistance in vitro (Osborne et al, 2003), in a similar way as it did a decreased level of NCoR corepressor (Lavinsky et al, 1998).…”

Src Continues Aging: Current and Future Clinical Directions

“…Many of the same Src modulations occur with antiestrogen therapies. Elevated Src levels have been shown to be associated with tamoxifen resistance, and treatment with a Src inhibitor prevented or reversed the development of this resistance (53,54). Two phase II studies are exploring the combination of these antiestrogen agents and Src inhibitors in randomized trials in breast cancer.…”

The Crucial Role of c-Src Tyrosine Kinase in Bone Metabolism

“…Indeed, it has been demonstrated that the expression of a constitutively active c-Src attenuated the sensitivity of MCF7 breast cancer cells to tamoxifen (Morgan et al, 2009). In the same cell line the synergistic interaction between ER, EGF receptor and c-Src enhanced tumour cell responsiveness to mitogenic stimuli, allowing their survival also in the presence of tamoxifen (Yue et al, 2007).…”