Hox Genes in Normal Breast Development and Breast Cancer
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: Cancer is intimately related to the process of development and growth. Every gene implicated in progression to a cancerous phenotype has at least one role, and often multiple roles, during the course of normal growth and development of an embryo. Here, we propose to study Hox genes in the mammary gland because they play important roles in normal breast development, and may have implications in breast cancer.
 
 
 
 
 
 
 
 The mammary gland in many respects is an embryonic organ because it undergoes its major morphological and functional maturation (differentiation) after birth. Dr. Bissell's laboratory and others have found that a set of important developmental genes, known as Hox genes, are present in normal breast cells and furthermore, breast tumors have Hox genes that are not found in the normal breast. We will concentrate on two Hox genes, Hoxa-1 and Hoxb-7, both of which are found in breast epithelial cells cultured on tissue culture plastic outside the animal's body. Studies in the breast in animals have shown that Hoxb-7 is present throughout mammary gland development except during lactation. However, Hoxa-1 was found only in breast tumors. Why is Hoxa-1 present in normal breast cells in culture but absent from the normal breast?
 
 
 
 
 
 
 
 Breast epithelial cells in the body "sit" on a thin layer of a specialized network of globular proteins referred to as extracellular matrix. This protein network provides important positional and practical information that is required for mammary epithelial cell function, including milk production and secretion. Breast epithelial cells in culture are not functional unless in contact with an extracellular matrix that mimics their environment in the body. Under these conditions, we found no Hoxb-7 and Hoxa-1 in normal mammary epithelial cells. We therefore believe that extracellular matrix regulates these genes in the body. Hoxa-1 continues to be present in tumor cells, however, even in the presence of extracellular matrix, indicating that this regulatory mechanism is disrupted in tumor cells.
 
 
 
 
 
 
 
 Based on the presence of Hoxb-7 during stages of branching, and on the absence of Hoxb-7 during lactation in the breast, I propose to explore whether Hoxb-7 is involved in morphogenesis of the breast when the animal is not lactating, and whether this gene must be suppressed so the animal can lactate. 
 
 
 
 
 
 
 
 Although the presence of Hoxa-1 and breast cancer strongly coincide, the exact role of Hoxa-1 in breast tumor formation and progression has not yet been addressed. Here I propose to use a genetic engineering approach to increase Hoxa-1 in normal breast cells in order to investigate the effect of a deregulated Hoxa-1 gene on normal breast development in cell culture assays and inside the body. Furthermore, using other techniques, Hoxa-1 expression will be inhibited in tumor cells. Both these engineered cells will then be tested for their potential to grow and to invade in the mouse breast.
 
 
 
 
 
 
 
 Hox genes have been shown previously to have tumorigenic potential when increased in fibroblasts and thus, are often defined as 'cancer genes'. Indeed, if abnormally present, they have the potential to misregulate a large number of genes, and thus, to contribute to cancer pathology. It is therefore conceivable that Hox genes might be targets of future gene therapies in the prevention and treatment of cancer.