Dopamine D1 receptor agonists inhibit lung metastasis of breast cancer reducing cancer stemness.

The leading causes of death in breast cancer patients are disease recurrence and metastasis. Growing evidence has suggested that metastasis possibly originates from cancer stem-like cells (CSCs). Previous studies indicated dopamine decreased CSC frequency through activating dopamine D₁ receptor pathway. Hence, this study explored the efficacy of two dopamine D₁ receptor agonists in lung metastasis of breast cancer and the preliminary mechanism. The two dopamine D₁ receptor agonists, fenoldopam (FEN) and l-stepholidine (l-SPD), performed well in decreasing lung metastasis in 4T1 breast cancer model. And the cGMP in the primary tumor was significantly elevated while cAMP mildly elevated in FEN and l-SPD dosing groups. CSC markers (CD44⁺/CD24^- and ALDH⁺) and MMP2 in 4T1 primary tumor were repressed after dopamine D₁ receptor agonist administration while E-cadherin up-regulated. FEN and l-SPD also inhibited cancer stemness and cell motility in vitro, and the inhibitory effects could be reversed by dopamine D₁ receptor antagonist SCH23390. Besides, FEN impacted the white blood cell increase caused by breast cancer disease showing decreased neutrophils but increased lymphocytes. Drug safety was verified in aspects of body weight, organ index and tissue section. In conclusion, dopamine D₁ receptor agonists FEN and l-SPD showed efficacy in inhibiting metastasis along with good safety in breast cancer, thus providing an alternative for anti-metastasis therapy in the future. Furthermore, this study also indicates that dopamine D₁ receptor may be a possible target for metastatic breast cancer treatment and even other cancers at a late stage.