How does estrogen work on autophagy?

Macroautophagy/autophagy is vital for intracellular quality control and homeostasis. Therefore, careful regulation of autophagy is very important. In the past 10 years, a number of studies have reported that estrogenic effectors affect autophagy. However, some results, especially those regarding the modulatory effect of 17 beta-estradiol (E2) on autophagy seem inconsistent. Moreover, several clinical trials are already in place combining both autophagy inducers and autophagy inhibitors with endocrine therapies for breast cancer. Not all patients experience benefit, which further confuses and complicates our understanding of the main effects of autophagy in estrogen-related cancer. In view of the importance of the crosstalk between estrogen signaling and autophagy, this review summarizes the estrogenic effectors reported to affect autophagy, subcellular distribution and translocation of estrogen receptors, autophagy-targeted transcription factors (TFs), miRNAs, and histone modifications regulated by E2. Upon stimulation with estrogen, there will always be opposing functional actions, which might occur between different receptors, receptors on TFs, TFs on autophagy genes, or even histone modifications on transcription. The huge signaling network downstream of estrogen can promote autophagy and reduce overstimulated autophagy at the same time, which allows autophagy to be regulated by estrogen in a restricted range. To help understand how the estrogenic regulation of autophagy affects cell fate, a hypothetical model is presented here. Finally, we discuss some exciting new directions in the field. We hope this might help to better understand the multiple associations between estrogen and autophagy, the pathogenic mechanisms of many estrogen-related diseases, and to design novel and efficacious therapeutics.