Acquired Resistance to Tamoxifen Is Associated with Loss of the Type I Insulin-like Growth Factor Receptor: Implications for Breast Cancer Treatment

Abstract

The role of the insulin-like growth factor (IGF) system in breast cancer is well defined, and inhibitors of this pathway are currently in clinical trials. The majority of anti-IGF1R clinical trials are in estrogen receptor–positive patients who have progressed on prior endocrine therapy; early reports show no benefit for addition of IGF1R inhibitors to endocrine therapy in this setting. In this study, we examined the effectiveness of IGF1R inhibitors in vitro by generating tamoxifen-resistant (TamR) cells. We found that TamR cells had diminished levels of IGF1R with unchanged levels of insulin receptor (IR), and failed to respond to IGF-I–induced Akt activation, proliferation, and anchorage-independent growth while retaining responsiveness to both insulin and IGF-II. The IGF1R antibody dalotuzumab inhibited IGF-I–mediated Akt phosphorylation, proliferation, and anchorage-independent growth in parental cells, but had no effect on TamR cells. An IGF1R tyrosine kinase inhibitor, AEW541, with equal potency for the IGF1R and IR, inhibited IGF-I-, IGF-II-, and insulin-stimulated Akt phosphorylation, proliferation, and anchorage-independent growth in parental cells. Interestingly, AEW541 also inhibited insulin- and IGF-II–stimulated effects in TamR cells. Tamoxifen-treated xenografts also had reduced levels of IGF1R, and dalotuzumab did not enhance the effect of tamoxifen. We conclude that cells selected for tamoxifen resistance in vitro have downregulated IGF1R making antibodies directed against this receptor ineffective. Inhibition of IR may be necessary to manage tamoxifen-resistant breast cancer.

A molecular model for the mechanism of acquired tamoxifen resistance in breast cancer

“…4B). Our observations precisely define the mechanisms underlying the paradoxical finding in vivo that acquired resistance to TAM is associated with loss of total IGF-1R (34, 37, 40) but keep (40) or gain of phosphorylated IGF-1R (34, 37). In contrast to the result that the non-genomic action of ER can rapidly (within minutes) activate IGF-1Rβ (27), we detected increased phosphorylation of IGF-1Rβ by 4-OHT after 24 hours (Fig.…”

“…Membrane-associated growth factor receptors, such as IGF-1R are another permissive components resulting in TAM resistance (34-37). IGF-1R is regulated by E 2 in an ER-dependent manner (19, 38).…”

The function of membrane-associated molecules in acquired resistance to antiestrogens in breast cancer

“…Interestingly, 4-OHT is able to simultaneously enhance the non-genomic activity of ER and activates focal adhesion molecules to increase phosphorylation of IGF-1R [11,32] . Our observations precisely define the mechanisms underlying the paradoxical finding in vivo that acquired resistance to tamoxifen is associated with lower levels of total IGF-1R [11,17,28,33] but keep [33] or gain of phosphorylated IGF-1R [11,17,28] . Together, these results demonstrate that 4-OHT exerts distinct functions on nuclear ER and membrane-associated ER, which differentially affects the function of IGF-1R.…”

“…It is well known that cytoplasmic adapter proteins have the capacity to provide docking sites for the redistribution of a low percentage of ER [26] that functionally associates with the cell membrane, and facilitate the crosstalk between the ER and growth factor receptors [26,27] . Accumulating evidence has suggested that growth factor receptors, such as epidermal growth factor receptor (EGFR) [27] , IGF-1R [11,28,29] , and HER-2 [30] are implicated in acquired SERM resistance, but its precise contributions are not well understood. In our SERM-resistant cell model, levels of IGF-1R are increased by E2 in an ER-dependent manner [10,11] .…”

Post-menopausal vulvovaginal atrophy — an overview of the current treatment options

“…So far, the mechanism of choosing classical or non-classical pathway remains unknown. Oestrogen receptors also affect the activation of growth factors, such as EGFR, HER2/Neu and IGFR [15][16][17][18][19]. Sawczuk el al.…”