Role of IKKa in Mammary Gland Development
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: Understanding the mechanisms involved in development of normal breast (mammary glands in mice) tissue will allow us to better understand what goes wrong when the epithelial cells of the breast grow in a deregulated fashion and form a malignant tumor. Clear understanding of such basic mechanisms should provide us the means to design much more specific and effective therapies for breast cancer. The principal investigator had identified an enzyme, a specific protein kinase called IKK?, whose inactivation specifically prevents the extensive proliferation of the mammary gland epithelium that normally occurs during pregnancy. Circumstantial evidence suggests that IKK? may also be involved in stimulating the proliferation of breast cancer cells and in protecting them from killing by anti-cancer drugs. This proposal is to study how IKK? controls the proliferation of normal mammary epithelial cells, which make up the milk forming apparatus of the breast. Preliminary evidence suggests that IKK? is a specific regulator of breast cell proliferation, whose inhibition may not result in adverse effects on other tissues or physiological processes. 
 
 
 
 
 
 
 
 The major question that needs to be answered is how IKK? acts to control the development of the mammary gland, especially during pregnancy. We also would like to understand why the enzymatic activity of IKK? is so important for proliferation of mammary epithelial cells but is dispensable for most other physiological processes. The central hypothesis is that IKK? , which is a subunit of a larger enzyme called IKK that contains another enzymatic subunit related to IKK? becomes specifically active during pregnancy. Once IKK? is active it generates a signal that increases the production of a protein called cyclin D1 that stimulates the activity of the cell division machinery of mammary epithelial cells. Inhibition of cyclin D1 expression interferes with proliferation of breast epithelial cells and many breast cancers exhibit high levels of cyclin D1. Curiously, IKK? either becomes active or exerts its growth stimulating activity only in mammary epithelial cells. We would therefore like to understand why IKK? has such a restricted activity. The proposed experiments will be mostly carried out in vivo, i.e. in intact experimental animals and therefore will provide information that is of high physiological relevance. As an experimental animal, we will use the laboratory mouse because the development of the mammary gland of female mice is very similar to the development of the human breast. To determine the involvement of specific genes in this process, we will generate mutant mice with specific genetic defects known as knockout or knockin mice. To examine the development of mammary glands in these mice, we will use a variety of histological and biochemical techniques.
 
 
 
 
 
 
 
 The most exciting aspect of this project is that inhibition of the enzymatic activity of IKK? only interferes with the development of the mammary gland during pregnancy but has no adverse effect on development of other tissues and organs, viability, metabolism, fertility, behavior or general well being. Thus IKK? may be a highly specific regulator of breast development and may provide an outstanding target for development of drugs that inhibit the proliferation and increase the killing of breast cancer cells with hardly any side effects.