85P - HDAC6-mediated regulation of progesterone receptor: Implications for hormonal therapy in breast cancer

Background

Modulation of progesterone receptor (PR) expression and its functional crosstalk with estrogen receptor (ER), represent a potential approach for enhancing the response to hormonal therapy in breast cancer. Aberrant epigenetic alterations induced by histone deacetylases (HDACs) were massively implicated in dysregulating the function of hormone receptors. However, pan-HDAC inhibitors have shown limited clinical sucess due to the lack of efficacy and serious side effects. Therefore, targeting specific HDACs, like HDAC6, with isoform-selective inhibitors may enhance therapeutic outcomes to anti-hormonal drugs. Despite many reports demonstrating HDAC6's role in breast tumorgenesis, its contribution to hormone receptors regulation remains poorly undertstood. Here we set out to explore the role of HDAC6 in modulating PR expression and its impact on the response to hormonal therapy.

Methods

The correlation between HDAC6 and hormone receptors was investigated in patients’ tissues by immunohistochemistry (n=80) and publicly available data (n=3260) from breast cancer patients. We explored the effect of HDAC6 downregulation or overexpression as well as its catalytic inhibition in hormone receptor-positive and triple-negative cells. The molecular investigations involved using western blot, immunofluorescence, real-time PCR, RNA-seq analysis and chromatin immunoprecipitation.

Results

Based on our in-silico and immunohistochemistry analyses, HDAC6 levels are negatively correlated with PR status in breast cancer tissues. Chromatin immunoprecipitation (ChIP) assay demonstrated that HDAC6 enriched at the promoter site of the PGR-B gene in hormone receptor-positive and triple-negative breast cancer (TNBC) cells. The selective targeting of HDAC6 resulted in the enrichment of the H3K9 acetylation mark at the PGR-B gene promoter region and enhanced the expression of PR-B in both cells. Notably, the addition of HDAC6 inhibitor potentiated the effects of anti-ER and anti-PR drugs mainly in TNBC cells.

Conclusions

These data highlight the role of HDAC6 in regulating PR expression and provide a promising therapeutic approach for boosting breast cancer sensitivity to hormonal therapy.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

University of Sharjah.

Funding

Research Funding Department at the University of Sharjah [grant number 2101110354] and L'Oréal-UNESCO for Women in Science Middle East program [grant number 4500407531].

Disclosure

All authors have declared no conflicts of interest.