Study of the Molecular Signaling of Chronic Stress in Promoting Breast Cancer Development to Prevent and Reduce Breast Cancer Incidence
Abstract
This study addresses the Overarching Challenge to prevent breast cancer. Breast cancer remains to be one of the most common cancers and a leading cause of cancer-related deaths in women despite significant advances in screening approaches, allowing for early detection of the disease, as well as continuous evolution of targeted therapies. The known risk factors for breast cancer include family history, Li-Fraumeni syndrome, atypical hyperplasia of the breast, late age at first full-term pregnancy, and late menopause. Because some of these risk factors are not modifiable, novel, safe, and effective strategies for prevention of breast cancer are highly desirable. Epidemiological studies have strongly suggested that chronic stress has significant negative influences on the onset, progression, and mortality of breast cancers. For instance, disruption of marriage, extreme stress, and low social support are related to increased risk of breast cancer. However, currently, the role of chronic stress in breast cancer development remains elusive due to the lack of direct evidence from animal models, and furthermore, the underlying mechanisms remain unclear, which hinders the development of effective and safe chemopreventive strategies for breast cancer. Using chronic restraint mouse model, a well-established model that mimics chronic stress in humans, we established the mouse system that directly demonstrates that chronic stress promotes breast cancer development in MMTV-neu mice, a mouse model that is prone to develop spontaneous breast cancer. Tumor suppressor p53 plays a central role in preventing cancer development. The attenuation or loss of p53 contributes greatly to breast cancer development. Our recent studies found that chronic restraint greatly decreases p53 function, which is mediated by glucocorticoids, a major neurohormone elevated during chronic stress. p53 maintains the genomic stability by preventing the accumulation of DNA damage, which could lead to DNA mutations and tumorigenesis in cells. The downregulation of p53 under the chronic stress condition may increase DNA damage, which could be an important mechanism by which chronic stress promotes the initiation and development of breast cancer. Indeed, our preliminary studies strongly suggest that chronic stress increases DNA damage in the breast tissue through the downregulation of p53 function mediated by glucocorticoids. Natural products, including L-theanine, an unique amino acid of tea, and vitamin C, are well known to decrease the levels of serum glucocorticoids to reduce stress. These results prompt us to hypothesize that L-theanine and vitamin C can prevent breast cancer development promoted by chronic stress through reducing the levels of serum glucocorticoids to re-activate p53, which in turn prevents DNA damage. To test our hypothesis, we plan to (1) test whether chronic stress downregulates p53 function through glucocorticoids to increase DNA damage and promote breast cancer development. In this aim, we will study the effect of chronic restraint on breast cancer development in MMTV-neu mouse model in detail to directly establish the role of chronic stress in breast cancer development. We will then test whether chronic restraint and corticosterone (a major glucocorticoid elevated under stress in mice) increase DNA damage in mouse breast tissues. We will further test whether chronic restraint increases DNA damage and promotes breast cancer development mainly through downregulating p53 function by comparing the effects of chronic restraint on DNA damage and breast cancer development between MMTV-neu mice with and without p53 expression in mammary glands. (2) We will study whether L-theanine and vitamin C prevent DNA damage and breast cancer development promoted by chronic stress through suppression of glucocorticoids to re-activate p53. In this aim, we will determine the effect of L-theanine and vitamin C on the levels of glucocorticoids i
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610358
Entities
People
- Wenwei Hu
Organizations
- Rutgers University
- United States Army