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

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 (Tam R) 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 Tam R 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.

Matrix Metalloproteinase-1 (MMP1) Upregulation through Promoter Hypomethylation Enhances Tamoxifen Resistance in Breast Cancer

“…MMP1 has also been shown to crosstalk with the IGF pathway by degrading IGFBP-1 that binds IGF with high affinity. Elevated IGFBP-1 expression has been reported in tamR MCF-7 and T-47D breast cancer cells, suggesting an association between tam resistance and IGFBP-1 accumulation [ 41 ]. Second, MMP1 might induce tam resistance by acting independently through previously identified routes including ER, EGF, or IGF pathways.…”

Progression from Monoclonal gammopathy of undetermined significance of the immunoglobulin M class (IgM-MGUS) to Waldenstrom Macroglobulinemia is associated with an alteration in lipid metabolism

“…We identified a few unique proteins in WM but not in MGUS samples, including IGFBP1, TFRC and Hemicentin 2 (HMCN2). Previous data have reported increased expression of IGFBP1 and its association with an elevated risk of prostate or pancreatic cancer [ 29 , 30 ] or resistance to therapy in breast cancer [ 31 ]. While TFRC is associated with iron metabolism and anemia [ 32 ], the presence of TFRC in the serum of the patients with Hodgkin or non-Hodgkin's lymphoma is shown to correlate with disease severity rather than iron-deficiency anemia [ 33 ].…”

Integrated Transcriptomic Analysis Revealed Hub Genes and Pathways Involved in Sorafenib Resistance in Hepatocellular Carcinoma

“…Through a genome-wide RNA interference screen, IGFBP1 was identified as one of the novel genes causing cellular resistance to neratinib [ 45 ]. Molecular mechanistic understanding has revealed that IGFBP1 is a key component of G protein-coupled estrogen receptor 1 (encoded by GPER1 ) which regulated the sensitivity of breast cancer cells to tamoxifen [ 46 , 47 ], and the resistance induced by RG7388 (MDM2 inhibitor) in glioblastoma [ 48 ]. Another study showed that reduction in insulin-like growth factor I (encoded by IGF-I ) mediated part of the starvation-dependent differential stress resistance [ 49 ].…”