Oncobioenergetics of Breast Carcinogenesis
Abstract
At present it is not clear what makes the breast susceptible to cancer development. However, different breast developmental stages that are vulnerable to the onset of cancer have been already established. The most vulnerable stages are fetal, pubertal, postpartum involution (retrograde change that result in normal size after delivery), and perimenopause (a stage before menopause). This high-risk/high-gain proposal is aimed at identifying the mechanism for increased susceptibility to breast cancer risk at pubertal stage of breast development. Puberty is the most important stage that has been studied in detail to establish the relationship between timing of exposure to cancer-causing agents (carcinogens) and risk of breast cancer development. For example, as in the case of atomic bomb explosions in Hiroshima and Nagasaki and Chernobyl tragedy, women exposed to radiation as teenagers (pubertal) were more susceptible to breast cancer later in life than those who are exposed as adults. Similarly, pubertal exposures to DDT, alcohol, and cigarette also leads to greater breast cancer risk. In support of these observations in humans, animal models of breast cancer also established that the risk is set by the timing of exposure to carcinogens, especially at puberty. However, the mechanism for such an increased susceptibility is not well understood. In order to explain this phenomenon, we proposed the concept of field effect or field carcinogenesis effect. Carcinogenesis is defined as the process of development cancer. The concept of field carcinogenesis effect suggests that cancer is developed not as an isolated event occurring in a cell but an event that involves several cells in a field of tissue. It suggests that the fields have a characteristic feature that supports cancer development compared to the tissues that reside outside the field. In our preliminary studies, we found in experimental rats that during puberty, metabolism of mammary gland switches towards a metabolism that resembles cancer cells (a hallmark of cancer) and establishes a tissue environment that has been shown to induce many inherited cancers such as glioma and renal cancers. Thus, exposure to carcinogens during puberty may increase the susceptibility to cause mutations and initiate the development of cancer. A similar metabolic change has been reported in cells with BRCA1 mutations, a very common gene mutation found in patients with inherited breast cancer. Therefore, in this proposal, the main objective is to determine (i) the metabolic features of mammary gland at different stages of development and (ii) whether switching to a cancer-like metabolism would increase the vulnerability to the onset of mammary cancer. This proposal thus addresses the following Breast Cancer Research Program overarching challenges: identify determinants of breast cancer initiation, risk, or susceptibility. This study will have significant impact on eradicating breast cancer in the following ways. (1) It addresses the key basic mechanistic questions for the increased vulnerability of mammary gland to carcinogens at puberty and will have significant impact on our understanding of the molecular mechanisms of breast cancer development. (2) This study is to lay a strong foundation for the introduction of the concept of prophylactic therapeutic and preventive approaches limited to a short, specific developmental window [puberty] in a woman s life for the prevention and treatment of breast cancer later in the life in high-risk groups. (3) As exercise and caloric restriction have an effect on metabolism, it allows us to design efficiently and test it in the clinics for the prevention of breast cancer. It also allows us to test mimetic that can produce therapeutic effect similar to exercise and caloric restriction for breast cancer prevention. (4) One of the epidemic of the modern society is metabolic syndrome and associated diseases like obesity, diabetes, etc.,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710156
Entities
People
- Praveen Vayalil
Organizations
- United States Army
- University of Alabama at Birmingham