Dissecting fibroblast growth factor-induced endocrine therapy resistance in breast cancer cells

Abstract The main challenge of effectively treating estrogen receptor-positive breast cancer is overcoming endocrine therapy resistance initiated by fibroblast growth factor signaling. Fibroblast growth factor-induced resistance can completely inhibit a therapeutic response to endocrine therapy, such as induced by the estrogen degrader Fulvestrant. Evidently, this sharply decreases a patient’s chance of survival. While fibroblast growth factor signaling is known to play an important role in endocrine therapy resistance, the molecular mechanisms driving this process remain unknown. Here, we expose alterations in signaling that are involved in treatment resistance by monitoring system-wide changes in the (phospho)proteome, and activation of the kinome, upon FGF-induced endocrine therapy resistance in breast cancer cells. We show that FGF treatment effectively degrades the estrogen receptor, likely via the transcription factor TWIST1, while initiating various phosphorylation-driven pathways that are known to support cell survival. Our data further indicate involvement of apoptosis inhibition through BAD activation, and AP-1 transcription factor activity mediated by JUN phosphorylation. In addition, our data reveals involvement of the transcription factor ENO1, which protein abundance anti-correlates with ER levels, in FGF-induced endocrine therapy resistance. The observed co-regulation of ENO1 with MYC indicates that its function in regulating cellular metabolism is driving this contribution to resistance. Altogether, our data provides a system-wide insight into FGF-induced resistance and can contribute to novel treatment options for endocrine therapy resistance in breast cancer patients.