The Interplay between the Cellular Response to DNA Double-Strand Breaks and Estrogen

Cancer development is often connected to impaired DNA repair and DNA damage signaling pathways. The presence of DNA damage in cells activates DNA damage response, which is a complex cellular signaling network that includes DNA repair, activation of the cell cycle checkpoints, cellular senescence, and apoptosis. DNA double-strand breaks (DSBs) are toxic lesions that are mainly repaired by the non-homologous end joining and homologous recombination repair (HRR) pathways. Estrogen-dependent cancers, like breast and ovarian cancers, are frequently associated with mutations in genes that play a role in HRR. The female sex hormone estrogen binds and activates the estrogen receptors (ERs), ERoc, ER(3 and G-protein-coupled ER 1 (GPER1). ERoc drives proliferation, while ER(3 inhibits cell growth. Estrogen regulates the transcription, stability and activity of numerus DDR factors and DDR factors in turn modulate ERoc expression, stability and transcriptional activity. Additionally, estrogen stimulates DSB formation in cells as part of its metabolism and proliferative effect. In this review, we will present an overview on the crosstalk between estrogen and the cellular response to DSBs. We will discuss how estrogen regulates DSB signaling and repair, and how DDR factors modulate the expression, stability and activity of estrogen. We will also discuss how the regulation of HRR genes by estrogen promotes the development of estrogen-dependent cancers.

Automated summary

Cancer development is often associated with impaired DNA repair and DNA damage signaling pathways. Estrogen has a regulatory role in the repair and cellular response to DNA double-strand breaks. There is a complex interplay between the cellular DNA damage response and the actions of estrogen, which may contribute to the development of estrogen-dependent cancers.