Abstract
Excess mental stress may harm health, and even accelerate cancer initiation and progression. One fourth of breast cancer patients suffer mental stress including anxiety, sadness, or depression, which negatively affect prognosis and survival. However, the regulatory mechanism is yet to be determined. Herein, we applied unpredictable stress stimuli to the breast tumor-bearing mice to establish a xenograft model of breast cancer suffering mental stress, followed by behavioral tests, tumor growth tracking, immune analysis, miRNA screening, and tumor cell proliferation analysis as well. As a result, increased stress hormone levels in serum, decreased percentage of T and NK cells in both blood and tumor samples and accelerated tumor growth in vivo were observed in the mice exposed to mental stress. Promoted cell proliferation was observed in both primary tumor cells derived from the stressed mice and 4T1 breast cancer cells treated with stress hormone corticosterone. In addition, a subset of miRNAs including miR-326, 346, 493, 595, 615, and 665 were identified through a miRNA screening with downregulation in tumors of the stressed mice. CCND1 was identified as a common target gene of miR-346 and miR-493, the top two most significantly downregulated miRNAs by stress exposure. The stress-miRNA-CCND1 signaling regulation of the tumor cell proliferation was further validated in 4T1 cells treated with corticosterone in vitro. GO terms and KEGG pathways analyses on the target genes of miR-346 and miR-493 revealed their involvement in the regulation of human cancer and neuron system, indicating the importance of non-coding genome in mediating the mental stress-induced cancer regulation. In conclusion, this study not only explored immune and nonimmune mechanisms through which mental stress exposure contributes to tumor growth in breast cancer, but also suggested a new therapeutic strategy for cancer patients suffering mental stress.
Highlights
Mental stress, as a natural part of life, is expressed by everyone from time to time
About one fourth of the patients with breast cancer suffer substantial psychological distress including anxiety or depression [24, 25], which belongs to mental stress
Long-term or excessive mental stress exposure contributes to the high mortality and poor survival of cancer patients [26], mainly due to the significant influence on the nervous system, hormone secretion, endocrine balance, immune function and cellular metabolism [7, 27]
Summary
As a natural part of life, is expressed by everyone from time to time. A 4.72-fold increase of breast cancer risk was demonstrated for those women exposed to mental stress from bereavement, illness, or divorce Those breast cancer patients suffering excessive anxiety or worrying about the illness showed a poorer prognosis [10, 11]. Multiple approaches of Mental stress exposure inhibited immune system in both tests demonstrated depressive-like behavior of the mice under blood and tumors mental stress condition, which was associated with promoted To determine the immune mechanisms mediating the stresstumor growth, increased secretion of corticosterone (CORT) and induced phenotypes in the tumor-bearing mice, peripheral blood decreased percentage of immune cells in vivo. A key natural killer (NK) cells in the blood of the stressed mice (Fig. 3G, regulator of the cell cycle, CCND1 was identified as a potential target gene of the top-two most significantly deregulated miRNAs. H). CD45 was expressed in the tumor-infiltrating T lymphocytes (TILs) cells which have
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