Adaptation to AI therapy in breast cancer can induce dynamic alterations in ER activity resulting in estrogen independent metastatic tumours

Purpose: Acquired resistance to aromatase inhibitor therapy is a major clinical problem in the treatment of breast cancer. The detailed mechanisms of how tumour cells develop this resistance remain unclear. Here, the adapted function of ER to an estrogen-depleted environment following AI treatment is reported. Experimental Design: Global ER-ChIPseq analysis of AI resistant cells identified steroid-independent ER target genes. Matched patient tumour samples, collected before and after AI treatment, were used to assess ER activity. Results: Maintained ER activity was observed in patient tumours following neoadjuvant AI therapy. Genome-wide ER-DNA binding analysis in AI resistant cell lines identified a subset of classic ligand dependent ER target genes which develop steroid independence. Kaplan Meier analysis revealed a significant association between tumours which fail to decrease this steroid independent ER target gene set in response to neoadjuvant AI therapy, and poor disease-free and overall survival (n=72 matched patient tumour samples, p=0.00339 and 0.00155 respectively). The adaptive ER response to AI treatment was highlighted by the ER/AIB1 target gene, early growth response 3 (EGR3). Elevated levels of EGR3 were detected in endocrine resistant local disease recurrent patient tumours in comparison to matched primary tissue. However, evidence from distant metastatic tumours demonstrates that the ER signalling network may undergo further adaptations with disease progression as estrogen-independent ER target gene expression is routinely lost in established metastatic tumours. Conclusions: Overall, these data provide evidence of a dynamic ER response to endocrine treatment which may provide vital clues for overcoming the clinical issue of therapy resistance.

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