Role of the signal transducer and activator of transcription-3 upon epithelial cell differentiation

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Cells in the body of an animal often stop dividing and change into specialized cells and tissues. This fundamental process is called "differentiation". If differentiation is disturbed, then the cells may divide uncontrollably and cause a variety of diseases such as cancer. *** We are proposing to study the mechanism of differentiation of breast epithelial cells, which normally produce milk. We have been using as model the cell line HC11 which is derived from breast and behaves in a manner that resembles their behavior in the animal; if prolactin, the lactation hormone is added to the growth medium, then they are converted into milk-producing cells.*** For differentiation to occur, HC11 cells must also adhere to one another. This happens through proteins on the cell surface called "cadherins" that stick to each other like “velcro”. Interestingly, our lab recently demonstrated that besides this structural role, cadherins also activate a protein called "Rac", which, in turn, activates “Stat3”. Since cell to cell adhesion is required for differentiation, which would activate Rac, we are proposing to examine the role of the cadherin/Rac/Stat3 pathway upon the differentiation of HC11 cells. *** Our preliminary results demonstrate an interesting phenomenon: Introduction of low levels of a hyperactive form of Rac (RacV12) into the cell increases differentiation, while high levels prevent differentiation and promote cell multiplication. We will now investigate the mechanism of differentiation by examining the effect of hyperactive forms of other cellular components that interact with Rac, such as Stat3, IL6 and others, by increasing or decreasing their activity in the cell using drugs or genetic methods, then examining the effect that these manipulations have upon differentiation. *** Anticipated benefits and significance: The project proposed may expose a novel pathway leading from cadherin engagement to Stat3 activation, as being a central determinant of the balance between cell differentiation vs multiplication, that is may be a key for the decision of the cell to follow one or the other of these fundamentally opposite paths. In practical terms, if eg a cancer is driven by activated Rac there would be no need for a drug to inhibit Rac completely to cure the cancer, since low residual levels would actually cause differentiation and reverse the cancer. The knowledge gained may be applicable to other types of situations where cadherin engagement and growth arrest are necessary, such as differentiation of fat cells, muscle or cartilage with a large variety of applications, such as immunity, cancer or embryonic development. *** The students who advance this research will obtain valuable expertise on Cell Biology mechanisms and make an impact in both Academic and industrial research.