Understanding Physiological Prevention of Breast Cancer: Effect of Early First Full-Term Pregnancy
Abstract
The two major overarching challenges this proposal will address are: (1) Prevent breast cancer and (2) identify determinants of breast cancer initiation, risk, or susceptibility. There is a fundamental gap in understanding how early pregnancy reduces the lifetime risk of developing breast cancer. Continued existence of this gap in knowledge represents an important problem; investigating the cellular physiology of this protection at systemic and local environment will lead to better understanding of how an early life event like pregnancy influences the risk of cancer later in life. The long-term goal is to understand the underlying mechanism of early pregnancy-induced protection against mammary cancer. The objective of this particular application is to identify how early pregnancy persistently modifies the systemic hormone system, in particular, the hypothalamic-pituitary axis, to reduce the risk of mammary cancer. Further, how the altered systemic environment influences the local microenvironment at the cellular level to reduce the risk of mammary cancer will be investigated. Identifying these physiological alterations will better our understanding of early pregnancy influences the risk of breast cancer development, which is still not clear. The central hypothesis is that the early pregnancy-associated protection against mammary cancer is caused by persistently diminishing the functional activity of hypothalamic-pituitary-mammary axis, which in turn alters the mammary epithelial-stromal interactions and mammary stem cell niche. This hypothesis has been formulated on the basis of preliminary data produced in the applicant s laboratory. The rationale for the proposed research is that understanding the fundamental cellular physiology that regulate mammary cancer development has the potential to translate into better understanding of the pathogenesis of breast cancer, which affects one out of every eight women in this country and more than a million women worldwide each year. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: (1) determine whether early pregnancy alters the hypothalamicpituitary-mammogenic axis; (2) investigate the interaction between mammary epithelium and stroma in response to systemically reduced levels of GH and PRL in early parity; and (3) determine whether early parity alters the stemness of mammary stem cells. Under the first aim, an already proven secretogogue treatment and perifusion approach will be used to test the functional capacity of hypothalamic-pituitary mammogenic axis. Under the second aim, the well-established in vitro cell culture and in vivo transplantation methods will be used to study the mammary epithelial-stromal interactions in relation to early pregnancy-induced alterations in GH and PRL. Finally, under the third aim, a well-standardized stemness screening technique will be used to identify the impact of early pregnancy on mammary stem cells. The approach is innovative because it utilizes a naturally occurring phenomenon like early pregnancy to understand protection against breast cancer. The proposed research is significant because it is expected to vertically advance and expand understanding of how to prevent/reduce the risk of breast cancer. Ultimately, such knowledge has the potential to develop novel and innovative strategies to reduce the risk of breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1710047
Entities
People
- Rajkumar Lakshmanaswamy
Organizations
- Texas Tech University Health Sciences Center
- United States Army