Importance of StAR-related lipid transfer domain-containing protein 3 (STARD3) in HER2-positive Breast Cancer Growth and Metastasis

The HER2-positive breast cancer subtype constitutes approximately 20% of invasive breast cancers, is characterized by the hyperproliferation of the human epidermal growth factor receptor 2 (HER2) and is associated with an unfavorable prognosis. Various HER2-targeted therapies have demonstrated positive effects and benefits for patients; however, resistance to such therapies poses a significant challenge. Beyond elucidating molecular mechanisms, co-amplified genes with HER2 have been implicated in enhancing cancer cell aggressiveness. In our investigation, we observed heightened expression of STARD3 in HER2-positive breast cancer tumor tissues, correlating with a poorer prognosis. Molecular analyses unveiled that the interaction between STARD3 and the HER2 protein, along with their co-expression, plays a role in promoting cancer cell growth. We validated that STARD3 overexpression elevates HER2 levels through direct interaction with HSP90 protein, inducing phosphorylated SRC and potentially safeguarding HER2 from degradation. Conversely, loss of STARD3 diminishes HER2 expression via lysosomal degradation. Furthermore, STARD3 knockdown hampers the cell cycle by decreasing cyclin D1 and increasing p27, while STARD3 overexpression induces cell cycle progression. Our findings suggest that developing STARD3-specific targeted anticancer drugs could be beneficial for treating HER2-positive breast cancer patients. Intriguingly, our study identified curcumin is an effective inhibitor of STARD3. Notably, applying curcumin to STARD3 knockdown cells showed a considerable combined effect on suppressing cancer cell proliferation and motility. These results underscore the pivotal role of STARD3 in regulating HER2 protein expression and drug resistance. Curcumin may represent a clinically applicable option for STARD3-targeted therapy, especially in patients resistant to HER2 therapy.