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.
The main goal of this proposal is to use human breast cancer cell xenograft model to test the hypotheses that combination treatments of an opioid agonist and a beta2-adrenergic antagonist will increase immune surveillance of breast cancers by activating cytolytic functions of immune cells due to crosstalk between these two subgroups of G protein?coupled receptors. The findings of these experiments will form a novel treatment strategy targeting both improving cytotoxic responses and reducing inflammation for better prognosis and treatment outcome of all subtypes of breast cancers.
