We examined the association between endogenous opioid β-endorphin, cancer progression and pain in a transgenic mouse model of breast cancer, with a rat C3(1) simian virus 40 large tumor antigen fusion gene (C3TAg). C3TAg mice develop ductal epithelial atypia at 8 weeks, progression to intra-epithelial neoplasia at 12 weeks, and invasive carcinoma with palpable tumors at 16 weeks. Consistent with invasive carcinoma at 4 months of age, C3TAg mice demonstrate a significant increase in hyperalgesia compared to younger C3TAg or control FVBN mice without tumors. Our data show that the growing tumor contributes to circulating β-endorphin. As an endogenous ligand of mu opioid receptor, β-endorphin has analgesic activity. Paradoxically, we observed an increase in pain in transgenic breast cancer mice with significantly high circulating and tumor-associated β-endorphin. Increased circulating β-endorphin correlates with increasing tumor burden. β-endorphin induced the activation of mitogenic and survival-promoting signaling pathways, MAPK/ERK 1/2, STAT3 and Akt, observed by us in human MDA-MB-231 cells suggesting a role for β-endorphin in breast cancer progression and associated pain.

我们用大鼠 C3(1) 猿病毒 40 大肿瘤抗原融合基因 (C3TAg) 研究了内源性阿片类药物 β-内啡肽、乳腺癌转基因小鼠模型中的癌症进展和疼痛之间的关联。C3TAg 小鼠在 8 周时发展为导管上皮异型性，在 12 周时发展为上皮内瘤变，在 16 周时发展为具有可触及肿瘤的浸润性癌。与 4 个月大的浸润性癌一致，与年轻的 C3TAg 或没有肿瘤的对照 FVBN 小鼠相比，C3TAg 小鼠的痛觉过敏显着增加。我们的数据表明，生长的肿瘤有助于循环β-内啡肽。作为μ阿片受体的内源性配体，β-内啡肽具有镇痛活性。矛盾的是，我们观察到具有显着高循环和肿瘤相关β-内啡肽的转基因乳腺癌小鼠的疼痛增加。增加的循环β-内啡肽与增加的肿瘤负荷相关。我们在人 MDA-MB-231 细胞中观察到 β-内啡肽诱导有丝分裂和促进存活的信号通路 MAPK/ERK 1/2、STAT3 和 Akt 的激活，这表明 β-内啡肽在乳腺癌进展中的作用和相关疼痛。