Estrogen stimulation induces centrosome amplification through estrogen receptor alpha-mediated DNA damage

Abstract Estrogen plays a critical role in breast cancer development. Estrogen exposure during puberty is implicated in the emergence of precancerous mammary cells exhibiting chromosomal alterations. The presence of two centrosomes at the onset of mitosis promotes accurate chromosome segregation; thus, centrosome amplification can cause chromosomal instability. Here, we revealed that estrogen receptor alpha (ERα) activated by estrogen induces DNA damage, causing centrosome amplification via DNA damage response signaling. Under estrogen stimulation, ERα generates DNA double-strand breaks, which activate polo-like kinase 1 (PLK1) at the centrosomes. Activated PLK1 induces premature centriole disengagement, resulting in centrosome amplification. In addition to full-length ERα, which is the major isoform, the shorter isoform ERα46 also induced DNA damage, resulting in centrosome amplification under estrogen stimulation. Our results present a potential mechanism by which estrogen induces chromosomal alterations. This study reveals a novel role for estrogen stimulation in breast cancer development.