Genetic Screen Identifies Insulin-like Growth Factor Binding Protein 5 as a Modulator of Tamoxifen Resistance in Breast Cancer

Abstract

Tamoxifen resistance is one of the overarching challenges in the treatment of patients with estrogen receptor (ER)-positive breast cancer. Through a genome-wide RNA interference screen to discover genes responsible for tamoxifen resistance in vitro, we identified insulin-like growth factor binding protein 5 (IGFBP5) as a determinant of drug sensitivity. Specific knockdown of IGFBP5 by retroviral infection with short hairpin RNAexpressing cassette in MCF7 human breast cancer cells (pRS-shIGFBP5) conferred tamoxifen resistance in vitro due to concomitant loss of ERα expression and signaling. IGFBP5 expression was also reduced in MCF7 cells selected for tamoxifen resistance in culture (TAMR). Both tamoxifen-resistant MCF7-TAMR and MCF7-pRS-shIGFBP5 cells could be resensitized to drug by treatment with exogenous recombinant IGFBP5 (rIGFBP5) protein. Treatment with rIGFBP5 protein in mouse tumor xenografts reversed the in vivo tamoxifen resistance of MCF7-pRS-shIGFBP5 cell-derived tumors by reducing tumor cell proliferation. IGFBP5 immunohistochemical staining in a cohort of 153 breast cancer patients showed that low IGFBP5 expression was associated with shorter overall survival after tamoxifen therapy. Thus, IGFBP5 warrants investigation as an agent to reverse tamoxifen resistance.

Mechanisms associated with resistance to tamoxifen in estrogen receptor-positive breast cancer (Review)

“…Previous in vitro studies have aimed to elucidate the role of IGF-1R in breast cancer resistance. A gene that confers resistance to tamoxifen is for IGF binding protein 5 (IGFBP5) (75). IGFBP5 is a secreted protein that inhibits growth factor binding to IGF-1R (76).…”

IGFBP-5 enhances epithelial cell adhesion and protects epithelial cells from TGFβ1-induced mesenchymal invasion

“…For example, IGFBP-5 expression has recently been shown to be associated with increased survival times in breast cancer patients as well as being responsible for maintaining sensitivity to tamoxifen (Ahn et al , 2010). In addition, overexpression of IGFBP-5 in MCF-7 xenografts inhibited tumour development in mice (Ahn, Elwi, 2010) whilst recent studies have demonstrated a tumour suppressor role for IGFBP-5 in ovarian cancer cells (Rho et al , 2008) in osteosarcoma (Su et al , 2011) and in breast cancer after foetal alcohol exposure (Polanco et al , 2010). An intriguing relationship between IGFBP-5 and tumour dormancy has also been described.…”

Detection of PIK3CA Gene Mutations with HRM Analysis and Association with IGFBP-5 Expression Levels in Breast Cancer

“…On the other hand, IGFBP5 expression has been found to correlate with prognosis, clinical outcome (Daigeler et al, 2010), survival (Ahn et al, 2010), response to therapy (Yamashita et al, 2009), and drug resistance (Taylor et al, 2010), either negatively or positively. IGFBP5 is one of the genes that has been shown to predict the prognosis of primary breast tumors in reverse tamoxifen resistance (Ahn et al, 2010). Moreover, lower expression levels of IGFBP5 are reported to be associated with shorter overall survival after tamoxifen (TAM) therapy.…”

“…Recent studies have linked insulin-like growth factor (IGF)-binding protein 5 (IGFBP-5) to metastasis by revealing increased IGFBP-5 expression in metastatic patients (Pekonen et al, 1992;McGuire et al, 1994;Huynh, 1998;Mita et al 2007). One study showed IGFBP5 expression is inversely related with tumorogenesis of breast cancer (Polanco et al, 2010), where in another study, IGFBP-5 is shown to be associated with increased survival of breast cancer patients (Ahn et al, 2010).…”