Hormonal Regulation of TGF Beta During Mammary 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: The development of both the normal breast and breast cancers are regulated by ovarian hormones, progesterone and estrogen. However, it has long been postulated that these hormones have their effects by inducing certain growth factors that regulate cell growth rates. We propose that transforming growth factor-b (TGF-b), which has been found in different studies to both promote and inhibit human breast cancer, is differentially regulated by estrogen and progesterone, and in turn that it mediates breast development.
 
 
 
 
 
 
 
 It is already well established that TGF-b can profoundly inhibit epithelial cell proliferation and morphogenesis. However, it is not known when this action occurs in the normal breast or how it is regulated. The activity of TGF-b is restrained by its production in a latent complex. TGF-b needs to be released from this complex in an extracellular process called activation in order to influence cells. Studies in our laboratory showed that certain antibodies recognize TGF-b only upon its release from the latent complex, i.e. following activation. We believe that activation is a primary regulator of TGF-b action and requires further study in mammary glands in order to understand the complex role of TGF-b in breast biology and cancer.
 
 
 
 
 
 
 
 We have used these antibodies to obtain preliminary data that indicate that the level of activation is variable in mouse mammary epithelial cells (the cells that line the milk ducts and give rise to most mammary cancers) and is associated primarily with periods of mammary gland growth. Our preliminary data show that the endbud, a multicellular structure necessary for ductal elongation, contains a population of cells with a lot of active TGF-b, in addition to proliferating cells and cells undergoing programmed cell death. Likewise during pregnancy, mammary cells are highly proliferative but TGF-b is present in a certain subset. Since TGF-b profoundly inhibits mammary epithelial cell proliferation in culture, activation during growth periods appears paradoxical. However, TGF-b can also induce cell death, or apoptosis, and apoptosis often accompanies periods of proliferation, perhaps in order to insure that growth stops at the appropriate moment, or in order to weed out damaged cells. In the proposed studies we will define the role of TGF-b during these physiological states by determining whether the TGF-b positive cells are undergoing proliferation or apoptosis. We will also determine whether TGF-b positive cells also express the receptors for these hormones.
 
 
 
 
 
 
 
 Our hypothesis is that during the two major periods of mammary growth, i.e. puberty and pregnancy, estrogen and progesterone differentially regulate TGF-b activity, which in turn both positively regulates apoptosis and negatively regulates proliferation. In combination with our TGF-b antibodies, we will use two new transgenic mouse models in which TGF-b or progesterone receptor have been compromised in order to define the contribution of TGF-b to hormonal regulation of mammary growth and development.