Targeting the Opioidergic and Adrenergic Systems to Control Breast Cancers

乳腺肿瘤的分子亚型各不相同（管腔A型、管腔B型、三阴性/基底样型和Her 2型）。 乳腺癌的差异在所有类型中都存在。四种亚型的患病率和预后 在美国，乳腺癌似乎因种族而异。最近的研究已经确定了免疫反应在 HER 2+和基底肿瘤的肿瘤微环境是一个重要的预后因素。我们最近 表明通过内啡肽细胞疗法减少身体压力的干预抑制了 致癌物诱导的大鼠乳腺肿瘤动物模型的发病率、生长、恶性率和转移 通过增加免疫活性和改变肿瘤微环境中的炎症条件。的 内啡肽细胞疗法对癌症生长的有益作用涉及阿片样物质能系统的激活， 抑制大鼠的肾上腺素能系统。我们假设，靶向两种药物的药物 阿片系统和β_2-肾上腺素能系统可能为所有的生长预防提供有效的治疗。 乳腺癌细胞的类型。此外，我们假设δ-阿片样物质的同时激活 受体和β 2-肾上腺素能受体的抑制将是最有效的。为了验证这些假设，我们 将使用已建立的乳腺癌细胞系和代表各种乳腺癌的原发性人肿瘤组织， 无胸腺裸鼠和人源化NSG小鼠中异种移植物中的肿瘤亚型。我们将确定 δ-阿片受体激动剂和β 2-肾上腺素能受体拮抗剂的联合治疗 降低异种移植物的生长和侵袭性。我们将确定这些药物对肿瘤细胞的作用 通过测量各种生物化学标记物和增殖、凋亡和凋亡的信号分子， 上皮间质转化我们将研究阿片类和肾上腺素能药物是否改变免疫细胞 影响肿瘤细胞的生理功能。此外，我们将评估阿片类药物之间的串扰是否 和肾上腺素能药剂是由于免疫细胞和/或乳腺肿瘤细胞上的受体二聚化。我们将 采用各种细胞和分子方法、受体学和基因敲除技术， 研究阿片类和β 2-肾上腺素能药物对乳腺癌细胞生长的分子作用， 进展 总之，这些研究应该显示阿片类激动剂和β 2-肾上腺素能受体激动剂联合使用的有效性。 用于预防各种类型的乳腺癌细胞生长的拮抗剂， 用于治疗患有各种亚型乳腺癌的患者。

Breast tumors vary in their molecular subtypes (luminal A, Luminal B, triple negative/basal-like and Her2 type). Disparities in breast cancer persist in all types. The prevalence rates and prognosis of the four subtypes of breast cancer appear to differ by race in the US. Recent studies have identified the immune response in the tumor microenvironment of both HER2+ and basal tumors an important prognostic factor. We have recently shown that intervention related to reduction of body stress via endorphin cell therapy into the brain suppresses carcinogen-induced mammary tumor incidence, growth, malignancy rate, and metastasis in rat animal models by increasing immune activities and altering inflammatory conditions in the tumor microenvironment. The beneficial effect of endorphin cell therapy on cancer growth involves activation of the opioidergic system and suppression of the adrenergic system in rats. We hypothesize that pharmacological agents targeting both the opioidergic system and beta2-adrenergic system might offer an effective therapy for growth prevention of all types of breast cancer cells. Furthermore, we hypothesize that simultaneous activation of delta-opioid receptors and suppression of beta2-adrenergic receptors will be most effective. To test these hypotheses we will employ established breast cancer cell lines and primary human tumor tissues that represent various breast tumor subtypes in xenografts in athymic nude rats and humanized NSG mice. We will determine the efficacy of a combined treatment of a delta-opioid receptor agonist and a beta2-adrenergic receptor antagonist in reducing the growth and invasiveness in xenografts. We will determine effects of these agents on tumor cell physiology by measuring various biochemical markers and signaling molecules of proliferation, apoptosis and epithelial mesenchymal transition. We will study whether opioidergic and adrenergic agents alter immune cell functions to affect tumor cell physiology. Furthermore, we will evaluate if the cross talk between opioidergic and adrenergic agents is due to receptor dimerization on immune cells and/or breast tumor cells. We will employ various cellular and molecular approaches, receptorology and gene knockdown techniques to investigate molecular actions of opioidergic and beta2-adrenergic agents on breast cancer cell growth and progression. Together these studies should show the effectiveness of combining an opioid agonist and beta2-adrenergic antagonist for preventing growth of various types of breast cancer cells that may be easily translatable to clinic for the treatment of patients with various subtypes of breast cancers.