Acquisition of estrogen independence induces TOB1-related mechanisms supporting breast cancer cell proliferation

Area of Science:

• Oncology
• Molecular Biology
• Systems Biology

Background:

• Estrogen receptor-positive (ER+) breast cancer often develops resistance to endocrine therapies targeting the estrogen pathway.
• Identifying novel therapeutic targets is crucial for overcoming treatment resistance in ER+ breast cancer.

Purpose of the Study:

• To investigate the molecular mechanisms underlying estrogen-independent survival in ER+ breast cancer.
• To identify new therapeutic targets for overcoming resistance to estrogen-targeted therapies.

Main Methods:

• A systems biology approach using small interfering RNA (siRNA) screening against an estrogen receptor (ER)- and aromatase-centered network.
• Identification of genes essential for estrogen-independent cell survival but dispensable in estrogen-dependent cells.
• Analysis of TOB1's role in cell cycle regulation and sensitivity to AKT and mammalian target of rapamycin (mTOR) inhibitors.
• Phosphoproteomic and mRNA profiling to elucidate signaling network reprogramming.

Main Results:

• 46 genes were identified as selectively required for estrogen-independent breast cancer cell survival.
• The tumor suppressor gene TOB1 was identified as a critical determinant of survival in estrogen-independent ER+ breast cancer cells.
• TOB1 depletion induced G1 phase arrest and enhanced sensitivity to AKT and mTOR inhibitors in estrogen-independent cells.
• TOB1 significantly reprogrammed signaling networks differently in estrogen-sensitive versus estrogen-resistant cells.

Conclusions:

• TOB1 plays a novel role in mediating the survival of estrogen-independent ER+ breast cancers.
• Combining TOB1 inhibition with AKT/mTOR inhibition presents a promising therapeutic strategy for ER+ breast cancer patients with resistance.
• These findings have potential translational significance for managing ER+ breast cancer.