Adrenergic receptor β2 activation by stress promotes breast cancer progression through macrophages M2 polarization in tumor microenvironment Adrenergic receptor;Breast cancer;Epinephrine;Macrophage polarization;Stress; Stress and its related hormones epinephrine (E) and norepinephrine (NE) play a crucial role in tumor progression. Macrophages in the tumor microenvironment (TME) polarized to M2 is also a vital pathway for tumor deterioration. Here, we explore the underlying role of macrophages in the effect of stress and E promoting breast cancer growth. It was found that the weight and volume of tumor in tumor bearing mice were increased, and dramatically accompanied with the rising E level after chronic stress using social isolation. What is most noteworthy, the number of M2 macrophages inside tumor was up-regulated with it. The effects of E treatment appear to be directly related to the change of M2 phenotype is reproduced in vitro. Moreover, E receptor $ADR{\beta}2$ involved in E promoting M2 polarization was comprehended simultaneously. Our results imply psychological stress is influential on specific immune system, more essential for the comprehensive treatment against tumors. [BMB Reports 2015; 48(5): 295-300]

The PI3K/Akt/GSK-3β/ROS/eIF2B pathway promotes breast cancer growth and metastasis via suppression of NK cell cytotoxicity and tumor cell susceptibility

Antiestrogen resistance is a major obstacle to endocrine therapy for breast cancers. Although reduced estrogen receptor-α(ER-α) expression is a known contributing factor to antiestrogen resistance, the mechanisms of ER-αdownregulation in antiestrogen resistance are not fully understood. Here, we report that ectopic zinc-finger E-box binding homeobox 1 (ZEB1) is associated with ER-αdeficiency in breast cancer cells and thus confers antiestrogen resistance. Mechanistically, ZEB1 represses ER-αtranscription by forming a ZEB1/DNA methyltransferase (DNMT)3B/histone deacetylase (HDAC)1 complex on the ER-αpromoter, leading to DNA hypermethylation and the silencing of ER-α. Thus, ectopic ZEB1 downregulates ER-αexpression and subsequently attenuates cell growth inhibition by antiestrogens, such as tamoxifen and fulvestrant. Notably, the depletion of ZEB1 by RNA interference causes ER-αpromoter demethylation, restores ER-αexpression, and increases the responsiveness of breast cancer cells to antiestrogen treatment. By studying specimens from a large cohort of subjects with breast cancer, we found a strong inverse correlation between ZEB1 and ER-αprotein expression. Moreover, breast tumors that highly express ZEB1 exhibit ER-αpromoter hypermethylation. Using a nude mouse xenograft model, we further confirmed that the downregulation of ZEB1 expression restores the responsiveness of breast cancer cells to antiestrogen therapyin vivo. Therefore, our findings suggest that ZEB1 is a crucial determinant of resistance to antiestrogen therapies in breast cancer.

PTEN has been studied in several tumor models as a tumor suppressor. In this study, we explored the role of PTEN in the inhibition state of polarized M2 subtype of macrophage in tumor microenvironment (TME) and the underlying mechanisms. To elucidate the potential effect in TME, RAW 264.7 macrophages and 4T1 mouse breast cancer cells were co-cultured to reconstruct tumor microenvironment. After PTEN was down-regulated with shRNA, the expression of CCL2 and VEGF-A, which are definited to promote the formation of M2 macrophages, have a dramatically increase on the level of both gene and protein in co-cultured RAW 264.7 macrophages. And at the same time, NHERF-1 (Na⁺/H⁺ exchanger regulating factor-1), another tumor suppressor has a similar tendency to PTEN. Q-PCR and WB results suggested that PTEN and NHERF-1 were consistent with one another no matter at mRNA or protein level when exposed to the same stimulus. Coimmunoprecipitation and immunofluorescence techniques confirmed that PTEN and NHERF-1 were coprecipitated, and NHERF-1 protein expression was properly reduced with rCCL2 effect. In addition, cell immunofluorescence images revealed a profound transferance, in co-cultured RAW 264.7 macrophages, an up-regulation of NHERF-1 could promote the PTEN marked expression on the cell membrane, and this form for the interaction was not negligible. These observations illustrate PTEN with a certain synergy of NHERF-1, as well as down-regulation of CCL2 suppressing M2 macrophage transformation pathway. The results suggest that the activation of PTEN and NHERF-1 may impede the evolution of macrophages beyond the M1 into M2 phenotype in tumor microenvironment.