Transcriptional activation of Nlp by estrogen-ERα in breast cancer

Estrogen Receptor-α (ERα) is the key transcription factor that regulates cell proliferation and homeostasis. In this pathway, estrogen plays an important role in genomic instability and cell cycle regulation processes and the mechanisms of its action are multifaceted. In this study, we showed that estrogen regulates genomic instability through promoting the expression of Nlp, a BRCA1-associated centrosomal protein which is involved in microtubule nucleation, spindle formation, chromosomal missegregation and abnormal cytokinesis. We demonstrated that the expression of Nlp is strongly associated with ERα and FOXA1 level in clinical breast cancer samples with poor clinical outcomes to breast cancer patients. Addition of estrogen in the ER-positive breast cancer cells resulted in elevation of NLP mRNA. Significantly, we identified that estrogen-ERα is capable of regulating Nlp expression through specifically binding ERα to the proximal region and the Estrogen Responsive Elements (ERE) enhancer in the distal region of NLP gene. Reporter assays demonstrated that estrogen directly activated Nlp promoter. ChIP assay results showed that E2-ERα directly bound to the EREs of Nlp. Therefore, overexpression of Nlp in breast cancer exhibits a hormone-dependent pattern, and estrogen participates in the regulation of genome instability and cell cycle in breast cancer cells partially through transcriptional activation of NLP gene. Overexpression of Nlp enhances the malignant progression of ERα-positive breast cancer cells in vitro, whereas knockdown of Nlp suppresses this biological effects in ERα-positive breast cancer cells. ERα/Nlp axis may serve as a promising target against breast cancer.