Identification of ANT2 as a Druggable Target for Endocrine-Resistant ERα-Positive Breast Cancer

Area of Science:

• Biochemistry
• Oncology
• Molecular Biology

Background:

• Endocrine therapy is standard for ERα-positive breast cancer.
• Acquired resistance to endocrine therapy is a significant clinical challenge.

Purpose of the Study:

• To identify natural compounds targeting ERα-positive breast cancer.
• To investigate the mechanism of action and therapeutic potential of perillyl alcohol (POH).

Main Methods:

• Screening of natural compounds against ERα-positive breast cancer cells.
• Chemoproteome analysis and molecular dynamics simulations to identify POH targets.
• Assessment of ANT2 depletion and POH effects on ERα levels and cell growth.
• RNA sequencing and lipid droplet analysis in resistant cells.
• In silico screening for additional ANT2 inhibitors.

Main Results:

• Perillyl alcohol (POH) was identified as a compound that reduces ERα protein levels.
• Adenine nucleotide translocase 2 (ANT2) was identified as a direct target of POH.
• ANT2 depletion and POH treatment inhibited growth in Tamoxifen- and Fulvestrant-resistant breast cancer cells.
• POH and ANT2 depletion impaired fatty acid elongation and increased lipid droplet accumulation.
• Venetoclax and nystatin were identified as potential ANT2 inhibitors.

Conclusions:

• Adenine nucleotide translocase 2 (ANT2) is a direct target of perillyl alcohol (POH).
• Targeting ANT2 offers a potential therapeutic strategy for endocrine-resistant ERα-positive breast cancer.
• POH and other ANT2 inhibitors demonstrate efficacy against resistant breast cancer models.