Acquired Tamoxifen Resistance in MCF-7 Breast Cancer Cells Requires Hyperactivation of eIF4F-Mediated Translation

Abstract

While selective estrogen receptor modulators, such as tamoxifen, have contributed to increased survival in patients with hormone receptor positive breast cancer, development of resistance to these therapies has led to the need to investigate other targetable pathways involved in oncogenic signaling. Approval of the mTOR inhibitor everolimus in the therapy of secondary endocrine resistance demonstrates the validity of this approach. Importantly, mTOR activation regulates eukaryotic mRNA translation. Eukaryotic translation initiation factor 4E (eIF4E), a component of the cap-dependent translation complex eIF4F confers resistance to drug-induced apoptosis when overexpressed in multiple cell types. The eIF4F complex is downstream of multiple oncogenic pathways, including mTOR, making it an appealing drug target. Here we show that the eIF4F translation pathway was hyperactive in tamoxifen resistant MCF-7L (TamR) breast cancer cells. While overexpression of eIF4E was not sufficient to confer resistance to tamoxifen in MCF-7L cells, its function was necessary to maintain resistance in TamR cells. Targeting the eIF4E subunit of the eIF4F complex through its degradation using an antisense oligonucleotide (ASO) or via sequestration using a mutant 4E-BP1 inhibited the proliferation and colony formation of TamR cells and partially restored sensitivity to tamoxifen. Further, use of these agents also resulted in cell cycle arrest and induction of apoptosis in TamR cells. Finally, use of a pharmacologic agent which inhibited eIF4E-eIF4G interaction also decreased the proliferation and anchorage dependent colony formation in TamR cells. These results highlight the eIF4F complex as a promising target for patients with acquired resistance to tamoxifen and potentially other endocrine therapies.

Hyperactive mTOR and MNK1 phosphorylation of eIF4E confer tamoxifen resistance and estrogen independence through selective mRNA translation reprogramming

“…Up-regulation of the abundance and/or activity of eIF4E, eIF4A, and/or eIF4G occurs widely in breast and other cancers and selectively up-regulates translation of certain mRNAs involved in survival, proliferation, and metastasis (Avdulov et al 2004;Braunstein et al 2007;Kim et al 2009;Silvera et al 2010;Badura et al 2012;Decarlo et al 2015). In fact, increased abundance of eIF4E has been shown to be important in resistance to a variety of PI3K-AKT-mTOR inhibitors (Avdulov et al 2004;Kim et al 2009;Silvera et al 2009aSilvera et al , 2010Bitterman and Polunovsky 2010;Hsieh et al 2010;Ilic et al 2010;Burris 2013;Bhat et al 2015;Fagan et al 2017).…”

Mechanisms of tRNA-derived fragments and tRNA halves in cancer treatment resistance

“…ABC transporter can efflux anticancer drugs across cell membranes, which is associated with drug resistance of many solid tumors [13,61]. The inhibition of eIF4F complex, including eIF4E, eIF4G, and eIF4A, enhances the sensitivity of various anticancer drugs, such as cisplatin sensitivity in non-small cell lung cancer (NSCLC) [62], trastuzumab and tamoxifen sensitivity in breast cancer [63,64], and enzalutamide and bicalutamide sensitivity in castration-resistant prostate cancer (CRPA) [65]. In addition, tRFs and tiRNAs can promote the assembly of stress granules (SGs) under stress conditions [40].…”

Translational opportunities for broad‐spectrum natural phytochemicals and targeted agent combinations in breast cancer

“…The lack of PTEN, overexpression and activation of HER2, AKT, MEK, ERK and loss of IGF1R following initial treatment are associated with increased resistance to tamoxifen in BC . The increased levels of ERα downstream effectors such as AP1, SP1, EIF4E, SOX9, LAMP3 and NFκB are also associated with resistance to endocrine therapy in BC . The increased expression and activation of nuclear receptor co‐activator 3 (NCOA3, also known as AIB), a co‐activator of ERα, is another mechanism of endocrine resistance in BC .…”

“…136,137 The increased levels of ERa downstream effectors such as AP1, SP1, EIF4E, SOX9, LAMP3 and NFjB are also associated with resistance to endocrine therapy in BC. [137][138][139][140][141] The increased expression and activation of nuclear receptor coactivator 3 (NCOA3, also known as AIB), a co-activator of ERa, is another mechanism of endocrine resistance in BC. 142 The overexpression of ER coactivators such as ER coactivator amplified in breast cancer 1 (AIB1) is an additional ERaindependent mechanism associated with tamoxifen resistance in BC.…”