Rac/STAT5 Signaling
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: Normal mammary gland function depends on proper interactions of breast epithelial cells with the surrounding tissue. Via these interactions, breast cells get guidance from their environment that regulates their responses to hormones, such as prolactin and estrogen, and enables normal growth and function. Disruption of these delicately balanced interactions will result in loss of tissue structure and function, resulting in malignant transformation of the cells and breast cancer. My objective is to examine the intracellular biochemical events that regulate normal breast cell function in a three-dimensional environment, and determine how inadvertent activation of these events may contribute to malignant transformation and treatment-resistant breast cancer. 
 
 
 
 
 
 
 
 I have found that two intracellular signaling molecules termed Rac and STAT5 are likely to function in concert and regulate normal breast function. Based on my preliminary findings, I hypothesize that the Rac/STAT5 complex functions as a molecular switch and controls the appropriate activation of mammary gland genes in response to prolactin and estrogen stimulation, allowing proper mammary gland function. My findings and recent published data further supports the hypothesis that a chronic activation of Rac/STAT5 signaling may in turn result in estrogen-independent growth and antiestrogen resistance, thereby aiding breast cancer development and drug-resistance. These hypotheses will be experimentally tested here. 
 
 
 
 
 
 
 
 Three general areas of study will be investigated. First, activation of STAT5 by Rac1 will be studied in normal breast cells in a three-dimensional culture model that mimics normal physiology of mammary gland. Antibodies that bind to activated STAT5, as well as the ability of STAT5 to bind specific DNA sequences, will be utilized to see Rac1 can activate STAT5 in normal breast cells. Second, the ability of activated STAT5 to regulate estrogen receptor action in normal breast cells will be studied. The ability of STAT5 to prevent the estrogen receptor from binding DNA and turning genes on will be studied, thereby elucidating the importance of STAT5-estrogen receptor interaction in normal breast cells. Third, the role of STAT5 in estrogen-independent tumor formation will be studied. A mutant STAT5 that is constantly active will be introduced into normal cells. Tumor formation and ability of the breast cancer cells to grow without estrogen, and in the presence of antiestrogens, such as tamoxifen, will be studied.
 
 
 
 
 
 
 
 Normal breast cells are difficult to study using conventional techniques because their interactions with each other and with proteins outside of the cell are critical for normal behavior. In order to overcome this, I will simulate the environment of breast cells by growing cells in a manner that mimics the 3-dimensional shape and extracellular environment of the cells. This is a novel approach that will allow experimental manipulation within a normal cell context. Hence, the behavior of normal cells can be studied and compared with cells that have become tumorigenic at a molecular level. This approach is anticipated to provide important information of normal breast biology and cancer progression.