Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis...

Area of Science:

• Oncology
• Epigenetics
• Molecular Biology

Background:

• Endocrine therapies target estrogen receptor alpha (ERα) but resistance mechanisms are not fully understood.
• Drug-specific adaptive resistance in breast cancer cells remains an area of investigation.

Purpose of the Study:

• To investigate if breast cancer cells adapt to endocrine therapies via drug-specific epigenetic reprogramming.
• To elucidate the mechanisms of resistance to aromatase inhibitors (AIs) and identify potential therapeutic targets.

Main Methods:

• Orthogonal genomics analysis of reprogrammed regulatory regions in resistant cell lines.
• In vitro and in vivo studies to assess cholesterol biosynthesis activation.
• Treatment with statins to target cholesterol biosynthesis and evaluate ERα binding and cell invasion.

Main Results:

• Resistance to aromatase inhibitors (AIs) emerges through drug-specific epigenetic reprogramming, involving topologically associating domains (TADs) and super-enhancers.
• AI-resistant cells exhibit activated endogenous cholesterol biosynthesis (CB), leading to constitutive ERα activation partly via 27-hydroxycholesterol.
• Targeting CB with statins reduces ERα binding and prevents cell invasion in resistant models.

Conclusions:

• Epigenetic reprogramming drives drug-specific resistance to endocrine therapies in breast cancer.
• Cholesterol biosynthesis is a key mediator of AI resistance by sustaining ERα activity.
• Epigenomic profiling can predict AI resistance in ERα-positive breast cancer patients, suggesting statins as a potential therapeutic strategy.