Intervention of chronic mild stress enhances growth of breast cancer and its changes in neuroendocrine and protein

Abstract

Breast cancer is the most common malignancy, which leads to both physical and psychological impairments. Accumulating evidence has suggested that negative mood is tightly related to initiation and progression of breast cancer. Despite the adverse impacts brought by psychological factors, especially depression, have been demonstrated as a key modulator for breast cancer progression in clinical trials, the laboratory evidence has not been well elucidated till now. The involved mechanisms are also not clear. In the present project, we evaluated the association between depression induced by chronic mild stress and breast cancer progression on the model of transgenic mice. This project is roughly divided into two parts. In the first part, the animal model was built to mimic breast cancer patients harboring chronic depression. The successful mice models were found with abnormal behaviors of depression, accompanying with physiological alterations (like helpless and reward-less behavior) as well as neurochemical changes (like 5-HT), suggesting depressive-like behaviors of mice models. The increasing tumor growth was largely attributable to depressive-like behaviors induced by chronic mild stress, presented as increased tumor incidence, enlarged tumor volume and relatively heavier tumor weight. In the second part, proteomics study using two-dimensional differential gel electrophoresis (2D-gels) was applied to explore the involved mechanisms. Next, we also identified protein targets using 2D-gels and validated using tandem mass spectrometry (MS/MS). Eight unique proteins in 16 spots were identified with significant differences between control and depression mice group. They are Thioredoxin 2 [Mus musculus], retinol-binding protein 1 [Mus musculus], eukaryotic translation initiation factor 5A, isoformCRA_e [Mus musculus], actin-related protein 2/3 complex subunit 5 [Mus musculus], ASL1/Suclg2 fusion protein [Mus musculus], odorant receptor S86 [Mus musculus], EndoA' cytokeratin (5' end put.); putative [Mus musculus], and dihydrolipoyllysine-residue acetyltransferase componentof pyruvate dehydrogenase complex, mitochondrial. All these proteins were involved in breast cancer progression at varying stages. In addition, we searched the identified proteins and found that Thioredoxin 2 (Th2) was the most potential marker linking depression with breast cancer development among the 8 candidate protein. It has been demonstrated that Th2 play a critical role in oxidative stress-induced cell apoptosis. The abnormal expression of Th2 is possibly triggered by redox pathway activation, which subsequently induces breast cancer and predicts poor prognosis in breast cancer. More importantly, Th2 has played a critical role in oxidative-stress-mediated depression. Therefore, our results largely suggested a potential role of Th2 in linking chronic depression with breast cancer development. However, further functional studies will be conducted to confirm this finding, which may, in turn, pave a way for clinical treatment among breast cancer patients with chronic depression.