Analysis of the Immunoexpression of Opioid Receptors and their Correlation with Markers of Angiogenesis, Cell Proliferation and Apoptosis in Breast Cancer

Abstract

Objective: Breast cancer is a disease of great concern. The prognosis of this tumor is related to its staging. Opioids are widely used to minimize pain in oncology clinics; however, the relationship between the administration of opioids and their effects on tumor cells has yet to be elucidated. Therefore, this study aimed to evaluate the immunoexpression of mu-(μ) and kappa-(κ) opioid receptors and their correlation with markers of angiogenesis, cell proliferation, and apoptosis in biopsies of breast tumors. Methods: Demographic data, tumor characteristics, opioid use, and prognostic factors were collected from medical records. After the selection of the excisional biopsies, immunohistochemistry was performed for μ-and κ-opioid receptors, vascular endothelial growth factor (VEGF), Ki-67, and TUNEL. Results: A significant predominance of Ki-67 and μ-opioid receptor immunoexpression in the lymph nodes was observed in patients administered opioid medications. The luminal A subtype showed higher apoptosis levels (TUNEL) compared to the luminal B subtype. Patients with T4 tumor who had recurrence demonstrated a reduced expression of κ-opioid receptors at the lymph node location. Correlation analyses between the μ and κ opioid markers, VEGF, Ki-67, and TUNEL showed that these findings are likely involved in the same mechanisms the cancer of T4 stage breast cancer. Conclusion:The κ-opioid receptor has a lower immunoexpression in nodal tumor metastasis with recurrence, whereas the μ-opioid receptor is directly related to expression of TUNEL-positive cells in tumors and indirectly to Ki-67 in nodal metastasis. Neither of the two receptors was expressed in the primary tumor or nodal metastasis in relation to VEGF.

Beta 2 adrenergic receptor and mu opioid receptor interact to potentiate the aggressiveness of human breast cancer cell by activating the glycogen synthase kinase 3 signaling

“…Also, B2AR antagonist PRO decreased proliferation, migration and invasion of TNBC and non-TNBC cells both in vitro and in vivo systems [ 11 , 29 , 57 , 58 ]. In the case of MOR signaling, significant predominance of Ki-67 and μ-opioid receptor immuno-expression in the lymph nodes was observed in breast cancer patients with opioid medications [ 59 ]. Also, MOR antagonist naloxone or naltrexone increased the cell death while decreased the cell metastasis in an animal model of TNBC [ 29 , 60 ].…”

Opioid Receptor-Mediated and Non-Opioid Receptor-Mediated Roles of Opioids in Tumour Growth and Metastasis

“…Changes in expression of μ, δ, or κ-opioid receptors in cancer cells or tissues are reported in various cancer types and overall, point to an increased expression in cancer. The majority of studies described an increase in μOR ( 18 – 22 ), while some reports showed no significant differences in μOR expression levels between the tumour and adjacent non-tumour tissues ( 23 , 24 ). No studies reported a decreased expression of OR in cancer.…”