Upregulation of IRS1 enhances IGF1 response in Y537S and D538G ESR1 mutant breast cancer cells.

5 years ago

Upregulation of IRS1 enhances IGF1 response in Y537S and D538G ESR1 mutant breast cancer cells.

Li, Lee, Oesterreich, Bahreini, Park, Chu, Wang, Levine

Increased evidence suggests that somatic mutations in the ligand binding domain of estrogen receptor (ERα/ESR1) are critical mediators of endocrine-resistant breast cancer progression. Insulin-like growth factor-1 (IGF1) is an essential regulator of breast development and tumorigenesis, and also has a role in endocrine resistance. A recent study showed enhanced crosstalk between IGF1 and ERα in ESR1 mutant cells, but detailed mechanisms are incompletely understood. Using genome-edited MCF-7 and T47D cell lines harboring Y537S and D538G ESR1 mutations, we characterized altered IGF1 signaling. RNA-sequencing revealed upregulation of multiple genes in the IGF1 pathway, including insulin receptor substrate-1 (IRS1), consistent in both Y537S and D538G ESR1 mutant cell line models. Higher IRS1 expression was confirmed by qRT-PCR and immunoblotting. ESR1 mutant cells also showed increased levels of IGF-regulated genes, reflected by activation of an IGF signature. IGF1 showed increased sensitivity and potency in growth stimulation of ESR1 mutant cells. Analysis of downstream signaling revealed the PI3K-Akt axis as a major pathway mediating the enhanced IGF1 response in ESR1 mutant cells. Decreasing IRS1 expression by siRNA diminished the increased sensitivity to IGF1. Combination treatment with inhibitors against IGF1R (OSI-906) and ER (fulvestrant) showed synergistic growth inhibition in ESR1 mutant cells, particularly at lower effective concentrations. Our study supports a critical role of enhanced IGF1 signaling in ESR1 mutant cell lines, pointing towards a potential for co-targeting IGF1R and ERα in endocrine resistant breast tumors with mutant ESR1.

Publisher URL: http://doi.org/10.1210/en.2017-00693

DOI: 10.1210/en.2017-00693