Background: Epidemiological studies have strongly suggested that chronic stress has significant negative influences on the onset, progression, and mortality of human breast cancers. However, currently, the role of chronic stress in breast tumorigenesis 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. Employing chronic restraint in mice, a well-established model that mimics chronic stress in humans, we established the mouse system to study the impact of chronic stress upon breast tumorigenesis in vivo. We found that chronic restraint promotes breast cancer development in MMTV-neu mice, a mouse model that is prone to develop spontaneous breast tumors. This result strongly suggests that chronic stress promotes breast tumorigenesis. Tumor suppressor p53 and its signaling pathway play a critical role in tumor suppression; loss or decrease of p53 function promotes breast tumorigenesis. Our recent studies show that chronic restraint greatly decreases p53 function, which is mediated by glucocorticoids elevated under chronic stress. p53 plays a critical role in maintaining the genomic stability and replication fidelity in cells. The downregulation of p53 under chronic stress may increase DNA damage, which could be an important mechanism by which chronic stress promotes breast tumorigenesis. Our preliminary studies show that chronic restraint and glucocorticoids increase DNA damage in a largely p53-dependent manner. These results suggest that chronic stress increases DNA damage in breast tissues through attenuation of p53 function mediated by glucocorticoids. Natural products, including L-theanine, a unique amino acid of tea, and vitamin C, are well known to reduce the levels of serum glucocorticoids in vivo to reduce stress. These findings together raise the possibility that L-theanine and vitamin C may have a chemopreventive effect through suppressing glucocorticoids in vivo to re-active p53, which in turn prevents DNA damage and breast cancer promoted by chronic stress.Overarching Challenge: This study aims to establish the role of chronic stress in promoting breast cancer development and understand its underlying molecular mechanisms. Furthermore, we will test whether reducing glucocorticoids by L-theanine and vitamin C re-activates p53 function and reduces DNA damage to prevent breast cancer promoted by chronic stress. This study addresses the Overarching Challenge to prevent breast cancer, and has the direct potential to develop a new strategy to prevent breast cancer.Objective/Hypothesis: We hypothesize that chronic stress promotes breast tumorigenesis and the attenuation of p53 function by elevated glucocorticoids during chronic stress and the resultant increased DNA damage is an important mechanism. We further hypothesize that L-theanine and vitamin C reduce the levels of serum glucocorticoids to prevent DNA damage and breast cancer promoted by chronic stress.Specific Aims: To test our hypothesis, our proposed studies have two linked specific aims:(1) To test the hypothesis that chronic stress attenuates p53 function through elevated glucocorticoids to increase DNA damage and promote breast cancer development in vivo.(2) To investigate whether L-theanine and vitamin C prevent DNA damage and breast cancer development promoted by chronic stress through reducing the levels of serum glucocorticoids to re-activate p53.Study Strategy:Aim 1: We will employ the MMTV-neu mouse model to: (1) characterize the effect of chronic restraint on breast cancer development in detail; (2) investigate whether chronic restraint as well as corticosterone (a major glucocorticoid elevated under stress in mice) increase DNA damage in mouse breast tissues; and (3) investigate whether chronic restraint increases DNA damage and promotes breast cancer development mainly through attenuating p53 function. The effects of chronic stress on DNA damage and breast cancer development will be compared between MMTV-neu mice with and without p53 in mammary glands. Aim 2: We will (1) determine the effect of L-theanine and vitamin C on the levels of glucocorticoids under chronic restraint in MMTV-neu mice; (2) investigate whether L-theanine and vitamin C reduce the promoting effect of chronic restraint on DNA damage in mouse breast tissues; (3) investigate whether L-theanine and vitamin C inhibit the promoting effect of chronic restraint on breast cancer development of MMTV-neu mice; and (4) investigate whether L-theanine and vitamin C re-activate p53 to prevent DNA damage and breast cancer development promoted by chronic restraint.Impact: The overall objective of this study is to study the molecular signaling of chronic stress in promoting breast cancer development and to develop an effective and safe strategy to prevent and reduce the breast cancer incidence, particularly for women under chronic stress. We anticipate that this study will (1) significantly increase our understanding of the role and molecular mechanism of chronic stress in breast tumorigenesis; and (2) have the direct potential to use natural products, L-theanine and vitamin C, as a safe and effective chemopreventive strategy for breast cancer promoted by chronic stress.
|Effective start/end date||8/15/16 → 8/14/19|
- Congressionally Directed Medical Research Programs (CDMRP)