Breast cancer is one of the most common cancers worldwide. As tumors grow, they often face hypoxia – low oxygen conditions. Cancer cells adapt to hypoxia by increasing glucose uptake to fuel their rapid growth. A protein called HIF-1α plays a key role in this process.
A new study by Wang et al. published in Oncogenesis has uncovered how another protein called DAB2IP acts as a tumor suppressor in breast cancer by inhibiting glucose uptake under hypoxic conditions. The researchers found that DAB2IP binds to HIF-1α and promotes its degradation via ubiquitination. This reduces the ability of breast cancer cells to take up glucose in low oxygen environments.
The team first analyzed human breast cancer databases and found that low DAB2IP expression correlated with worse patient survival. They then conducted experiments in breast cancer cell lines and mouse models with varying DAB2IP levels.Under hypoxic conditions, cells and tumors with low DAB2IP showed:
- Increased HIF-1α protein levels
- Higher glucose uptake
- Faster tumor growth
In contrast, overexpressing DAB2IP in breast cancer cells led to:
- Decreased HIF-1α due to increased ubiquitination and degradation
- Reduced glucose uptake
- Slower tumor growth in mice
The researchers propose that DAB2IP acts as a endogenous HIF-1α inhibitor by facilitating its ubiquitination and subsequent breakdown, thus limiting hypoxia adaptation and glucose utilization by breast cancer cells. These findings highlight the important tumor suppressive function of DAB2IP and its potential as a therapeutic target in breast cancer.In summary, this study reveals a new mechanism by which DAB2IP protein helps restrain breast cancer growth and progression, by impairing the ability of tumor cells to take up glucose under hypoxic conditions. Increasing DAB2IP levels could be a promising strategy to slow down breast cancer and improve patient outcomes.