Mechanisms of Fluid Transport in Human Mammary Epithelium
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: An abnormal accumulation of fluid occurs in the breasts of a large fraction of pre-menopausal women (&gt;40%). This condition, termed gross cystic disease, is the most common benign disease of the breast and leads to an increased cancer risk 2- 4 times higher than the general population. This proposal aims to study a fundamental but little appreciated property of mammary epithelia - their ability to transport fluid and the relationship between fluid transport and the secretion of electrolytes and proteins that are commonly found in the cysts of patients with breast cystic disease. Mammary epithelia and epithelia throughout the body have the same general structure and function, they are sheets of tightly connected cells that either surround and protect the organs they serve or line the cavities of secretory glands. Epithelial cells have two functionally and structurally distinct surfaces termed apical and basolateral membranes. These two membranes face different extracellular environments on either side of the cell and contain different sets of proteins that permit the movement of nutrients, ions and fluid from one extracellular space to another. There is currently nothing known about the plasma membrane and signaling mechanisms that regulate the movement of fluid across mammary epithelia. 
 
 
 
 
 
 
 
 Fluid transport measurements will be carried out using a technique originally developed in this laboratory for work in eye and lung epithelia where issues of fluid transport are central to understanding disease (retinal detachments and cystic fibrosis, respectively). The research is risky since there is no clear cell or molecular basis for understanding the transition from breast cystic disease to hyperplasia to breast cancer. The completion of this work will provide two important benefits. First, we will have identified the transport proteins and signaling mechanisms that mediate the movement of fluid (and ions) across two kinds of intact epithelial monolayer cultures, one that emanates from "normal" (or fibrocystic) epithelia and the other from breast cancer epithelia. Secondly, based on this information we will be able to develop a pharmacological strategy for reducing fluid secretion or increasing fluid absorption across mammary epithelial cultures. This would provide the initial step toward a therapeutic intervention aimed at the reduction or elimination of the pathological accumulation of fluid secreted by epithelia in breast cystic disease. This kind of intervention may slow or reverse the development of breast hyperplasia. The benefits of preventing abnormal accumulations of fluid in gross cystic disease are three-fold: (1) a possible reduction in cancer risk or disease progression; (2) a reduction or removal of the considerable pain that inevitably accompanies the fluid-induced intracystic tension; (3) the removal of an impediment that continues to cause misdiagnosis of breast cancers by primary care physicians.