PI3K/mTOR mediate mitogen-dependent HDAC1 phosphorylation in breast cancer: a novel regulation of estrogen receptor...

Area of Science:

• Epigenetics and Cancer Biology
• Molecular Oncology
• Signal Transduction Pathways

Background:

• Breast cancer development involves genetic/epigenetic changes and signaling pathway deregulation.
• Estrogen receptor alpha (ERα) downregulation contributes to endocrine resistance in breast cancer.
• PI3K/mTOR pathway and HDACs are emerging therapeutic targets for breast cancer, including hormone resistance.

Purpose of the Study:

• To investigate the cross-talk between the PI3K/mTOR pathway and Histone deacetylase 1 (HDAC1) in breast cancer.
• To elucidate the role of p70 S6 kinase (S6K1) in mediating the effects of mitogenic stimuli on HDAC1.
• To explore the therapeutic implications of targeting both pathways for breast cancer treatment.

Main Methods:

• Investigated mitogen-activated PI3K/mTOR pathway signaling in breast cancer cells.
• Assessed the phosphorylation of HDAC1 and its dependence on S6K1 activity.
• Analyzed HDAC1 recruitment to the ERα promoter.
• Evaluated the combined effects of mTOR and HDAC inhibitors on breast cancer proliferation.

Main Results:

• Mitogens activate PI3K/mTOR signaling, triggering HDAC1 phosphorylation dependent on S6K1 activity.
• S6K1 controls HDAC1-dependent transcriptional regulation of ERα levels upon mitogenic stimuli.
• HDAC1 recruitment to the ERα promoter is modulated by S6K1.
• Combined treatment with mTOR and HDAC inhibitors demonstrated an additive effect on inhibiting breast cancer cell proliferation.

Conclusions:

• A novel cross-talk exists between HDAC1 and PI3K/mTOR signaling pathways in breast cancer.
• S6K1 plays a crucial role in regulating ERα levels via HDAC1 phosphorylation in response to mitogens.
• Targeting both HDAC1 and PI3K/mTOR pathways simultaneously holds significant clinical potential for treating breast cancer, including endocrine-resistant forms.