Protective Role of Estrogen Receptor Beta in Mammary
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: The hormone estrogen has been implicated in the development of breast cancer. The physiological effects of estrogen are mediated by two isoforms of the estrogen receptor. Estrogen receptor alpha (ERα) has been extensively characterized as the major mediator of growth in the breast. Estrogen receptor beta (ERβ) was only recently identified and its function in the normal breast is presently unclear, however a protective role for ERβ has emerged in the last few years. ERβ is lost in a majority of breast tumors suggesting that loss of ERβ may be a step in the transition from normal breast tissue into a cancerous state. Therefore it has been proposed that the function of ERβ is to modulate proliferation induced by ERα during the growth and development of the normal mammary gland.
 
 
 
 
 
 
 
 Our long-term objective is to understand the biochemical mechanisms whereby ERβ plays a protective role in the normal mammary gland and determine if loss of ERβ contributes to breast cancer. To achieve this goal we must first determine the function of ERβ in the breast and identify the mechanisms by which it modulates growth during normal mammary gland development. We hypothesize that the function of ERβ in the normal breast is to inhibit ERα-induced growth by modulating genes through specific gene pathways, which will be identified in these studies. While we suspect the involvement of non-classical pathways, other potential pathways will be examined in these studies as well.
 
 
 
 
 
 
 
 First, a high-tech method called microarray analysis will be used to analyze the molecular signatures of cultured breast cells that express both ERα and ERβ compared to the same cell type in which only ERα is present. Data generated will provide mechanistic clues into pathways by which ERβ modulates genes regulated by ERα. Second, we use an animal model developed in our lab that contains an abundance of ERα, which results in increased mammary growth. Even more profound growth is observed in mice with a mutant ERα that functions through a non-classical pathway, leading us to believe that this pathway is important in mammary gland development and growth. These animals will be bred with mice lacking ERβ to determine if the absence ERβ inhibits mammary growth in a model in which growth has been maximized.
 
 
 
 
 
 
 
 These studies utilize high-throughput methods in which the expression of a large number of genes will be examined and will provide an astounding number of clues into the mechanistic pathways in which ERβ modulates growth in the breast. This will be more efficient than using traditional molecular techniques and has not been attempted before to address the role of ERβ in the normal breast. In addition we will combine two characterized animal models, generating a unique animal that will demonstrate the role of ERβ in a biological context in which growth is maximized. Mechanistic knowledge gained from these studies will result in an exciting opportunity to design preventive strategies that target protective pathways of ERβ.