Interaction of Naloxone and Estrogen Receptor in Breast Cancer

Majority of breast cancers are estrogen receptor (ER) positive. Due to resistance to known ER-based therapies, novel treatment targets and drugs are required to effectively treat ER-positive breast cancer. Opioids are often used to treat pain in breast cancer and promote tumor growth and metastases in rodent studies. Opioid receptor (OR) antagonists, such as naloxone, naltrexone and methylnaltrexone inhibit cancer progression and metastases. All three antagonists share structural similarities with the estrogen, 17β-estradiol (E2), and are therefore capable of binding to ER. Naloxone inhibits E2-induced human MCF-7 breast cancer cell proliferation and MAPK/ERK signaling. Additionally, naloxone also attenuates the activation of membrane bound/cytoplasmic ER and phosphorylation of the epidermal growth factor receptor. Naloxone blocks the E2-induced ER activation by precluding its binding to the co-activator and by directly competing with E2 for binding to ER. In addition to these direct interactions with ER, naloxone prevents the cross-talk of ER with mu opioid receptor (MOR), suggesting that activation of MOR may contribute to E2-induced ER activation. Since naloxone and structurally similar OR antagonists inhibit cancer progression and metastases, OR antagonists can be potentially developed for breast cancer treatment.