Abstract
The hormone estrogen (E2) binds the estrogen receptor to promote transcription of E2-responsive genes in the breast and other tissues. E2 also has links to genomic instability, and elevated E2 levels are tied to breast cancer. Here, we show that E2 stimulation causes a rapid, global increase in the formation of R-loops, co-transcriptional RNA-DNA products, which in some instances have been linked to DNA damage. We show that E2-dependent R-loop formation and breast cancer rearrangements are highly enriched at E2-responsive genomic loci and that E2 induces DNA replication-dependent double-strand breaks (DSBs). Strikingly, many DSBs that accumulate in response to E2 are R-loop dependent. Thus, R-loops resulting from the E2 transcriptional response are a significant source of DNA damage. This work reveals a novel mechanism by which E2 stimulation leads to genomic instability and highlights how transcriptional programs play an important role in shaping the genomic landscape of DNA damage susceptibility.
Highlights
The hormone estrogen (E2, 17b-estradiol) is essential for the development and function of mammary tissue (Bieche et al, 2001), stimulating a transcriptional program that drives breast cell proliferation
Hormone-free culture conditions cause estrogen receptor (ER)-positive cells to withdraw from the cell cycle, and low phosphorylation of the histone variant H2AX (P-H2AX) levels arise during normal DNA replication (Mirzoeva and Petrini, 2003)
We asked whether an increase in the percentage of cells in S phase following E2 stimulation could account for the increased P-H2AX signal
Summary
The hormone estrogen (E2, 17b-estradiol) is essential for the development and function of mammary tissue (Bieche et al, 2001), stimulating a transcriptional program that drives breast cell proliferation. E2 exposure is associated with an elevated risk of breast carcinogenesis (Liehr, 2000; Yager and Davidson, 2006). Breast cancers exhibit a large number of chromosomal abnormalities, including mutations and copy number alterations (Nik-Zainal et al, 2016). E2 leads to DNA damage in breast epithelial cells that express the estrogen receptor (ER) (Liehr, 2000; Williamson and Lees-Miller, 2011), and in rat models, E2 stimulation is causally linked to chromosome instability and aneuploidy (Li et al, 2004). Despite strong links between estrogen and genomic instability, the molecular mechanism by which E2 causes this instability in breast cancer is unclear
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