IGFBP-1 Expression Promotes Tamoxifen Resistance in Breast Cancer Cells via Erk Pathway Activation.

Yan Zheng,Kevin D Houston,Janel Y Sowers

doi:10.3389/fendo.2020.00233

Abstract

Insulin-like growth factor (IGF) system plays a significant role in many cellular processes, including proliferation, and survival. In estrogen receptor positive breast cancer, the level of circulating IGF-1 is positively associated with the incidence and at least 50% of cases have elevated IGF-1R signaling. Tamoxifen, a selective estrogen receptor modulator and antagonist for estrogen receptor alpha (ERα) in breast tissue, is a commonly prescribed adjuvant treatment for patients presenting with ERα-positive breast cancer. Unfortunately, tamoxifen resistance is a frequent occurrence in patients receiving treatment and the molecular mechanisms that underlie tamoxifen resistance not adequately defined. It has recently been reported that the inhibition of IGF-1R activation and the proliferation of breast cancer cells upon tamoxifen treatment is mediated by the accumulation of extracellular insulin-like growth factor binding protein 1 (IGFBP-1). Elevated IGFBP-1 expression was observed in tamoxifen-resistant (TamR) MCF-7 and T-47D cells lines suggesting that the tamoxifen-resistant state is associated with IGFBP-1 accumulation. MCF-7 and T-47D breast cancer cells stably transfected with and IGFBP-1 expression vector were generated (MCF7-BP1 and T47D-BP1) to determine the impact of breast cancer cell culture in the presence of increased IGFBP-1 expression. In these cells, the expression of IGF-1R was significantly reduced compared to controls and was similar to our observations in tamoxifen-resistant MCF-7 and T-47D cells. Also similar to TamR breast cancer cells, MCF7-BP1 and T47D-BP1 were resistant to tamoxifen treatment, had elevated epidermal growth factor receptor (EGFR) expression, increased phospho-EGFR (pEGFR), and phospho-Erk (pErk). Furthermore, tamoxifen sensitivity was restored in the MCF7-BP1 and T47D-BP1 upon inhibition of Erk phosphorylation. Lastly, the transient knockdown of IGFBP-1 in MCF7-BP1 and T47D-BP1 inhibited pErk accumulation and increased tamoxifen sensitivity. Taken together, these data support the conclusion that IGFBP-1 is a key component of the development of tamoxifen resistance in breast cancer cells.

Highlights

Insulin-like growth factor (IGF) signaling is a complex system that affects almost every organ in the human body via regulation of multiple cellular processes, such as proliferation, survival, mitogenesis, migration, senescence, angiogenesis, and autophagy [1, 2]
Insulin-like growth factor binding protein-1 (IGFBP1) induction in 4-hydroxytamoxifen (4-OHT)-treated breast cancer cells was shown to mediate the efficacy of 4-OHT [15]
To determine if insulin-like growth factor binding protein 1 (IGFBP-1) is critical for the development of tamoxifen resistance in breast cancer cells, the level of IGF binding proteins (IGFBPs)-1 in MCF7 parental cells (MCF7-P) and MCF-7 tamoxifen resistant cell (MCF7-TamR), as well as in T-47D parental (T47D-P) and T47DTamR was determined

Summary

Introduction

Insulin-like growth factor (IGF) signaling is a complex system that affects almost every organ in the human body via regulation of multiple cellular processes, such as proliferation, survival, mitogenesis, migration, senescence, angiogenesis, and autophagy [1, 2]. The IGF system consists of two natural ligands, insulinlike growth factor-1 (IGF-1) and IGF-2; two transmembrane receptors, insulin-like growth factor 1 receptor (IGF-1R) and IGF-2R; and six high affinity IGF binding proteins (IGFBPs) 1-6 [3]. In addition to the complexity of the IGF system, there is an increasing body of evidence showing the interactions between IGF pathway and other hormone signaling pathways suck as estrogen receptor (ER) pathway [9] and epidermal growth factor receptor (EGFR)

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Conclusion