Abstract
Breast cancer prognosis and response to endocrine therapy strongly depends on the expression of the estrogen and progesterone receptors (ER and PR, respectively). Although much is known about ERα gene (ESR1) regulation after hormonal stimulation, how it is regulated in hormone-free condition is not fully understood. We used ER-/PR-positive breast cancer cells to investigate the role of PR in ESR1 regulation in the absence of hormones. We show that PR binds to the low-methylated ESR1 promoter and maintains both gene expression and DNA methylation of the ESR1 locus in hormone-deprived breast cancer cells. Depletion of PR reduces ESR1 expression, with a concomitant increase in gene promoter methylation. The high amount of methylation in the ESR1 promoter of PR-depleted cells persists after the stable re-expression of PR and inhibits PR binding to this genomic region. As a consequence, the rescue of PR expression in PR-depleted cells is insufficient to restore ESR1 expression. Consistently, DNA methylation impedes PR binding to consensus progesterone responsive elements. These findings contribute to understanding the complex crosstalk between PR and ER and suggest that the analysis of ESR1 promoter methylation in breast cancer cells can help to design more appropriate targeted therapies for breast cancer patients.
Highlights
Estrogen and progesterone are the main players in the progression and outcome of breast cancers [1]
Comparing the ESR1 gene expression in T47D breast cancer cells and a derived clone selected for its low progesterone receptor (PR) expression (T47D-Y) [11], as previously observed [12], we confirmed that low PR expression is accompanied by a low expression of ESR1 at both the transcript and protein levels (Figure 1a,b, left panels)
Concomitant with the decrease of PR levels, RNA and protein amount of ESR1 decreased in short-hairpin RNA approach (shPR) cells compared to control cells
Summary
Estrogen and progesterone are the main players in the progression and outcome of breast cancers [1]. Both hormones act through their cognate receptors, estrogen receptor (ER) and progesterone receptor (PR) [1]. PR and ER exhibit enhanced binding to specific DNA sequences known as hormone-responsive elements, which are generally located within target gene enhancers or promoters [1,2]. The DNA-bound receptors orchestrate the assembly of large cofactor-containing protein complexes that can either positively or negatively affect gene transcription [1]. Hormone-activated ER and PR attached to the cell membrane can trigger rapid signaling by interacting with several kinases, which participate in hormonal gene regulation [1,3].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
