ESR1 mutations affect anti-proliferative responses to tamoxifen through enhanced cross-talk with IGF signaling

The rediscovery of estrogen receptor (ESR1) mutations in metastatic breast cancer is current clinical scenario. We have modeled the three most frequent ESR1 mutations using stable lentiviral vectors in human breast cancer cell lines, and determined that they confer relative resistance to tamoxifen (Tam) in a cell-type specific manner due to distinct epigenetic changes. Resistance was only observed with concomitant engagement and activation of the insulin growth factor signaling pathway (IGF1R). The ESR1 mutants also exhibited enhanced binding with insulin growth factor receptor beta (IGF1R). The selective estrogen degrader, fulvestrant, significantly reduced the anchorage-independent growth of ESR1 mutant-expressing cells, while the combination treatment with the mTOR inhibitor everolimus, restored Tam sensitivity. Since we detected relatively high frequencies of these three mutations in primary breast tumors, our results suggest that clinical targeted sequencing of both primary and metastatic tumors may be justified and comination therapies considered.

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Gelsomino L, Gu G, Rechoum Y, Beyer AR, Pejerrey SM, Tsimelzon A, Wang T, Huffman K, Ludlow A, Andò S, Fuqua SAW