The Functional Effect of an Amphiregulin Autocrine Loop on Inflammatory Breast Cancer Progression

Inflammatory breast cancer (IBC) is one of the most lethal forms of breast cancer. A strong correlation has been found between inflammatory breast cancer and high levels of the growth factor amphiregulin. Amphiregulin is known to activate the epidermal growth factor receptor (EGFR) which turns on genes involved in a number of functions including cell growth. Self-sustained activation of EGFR by amphiregulin is called an amphiregulin autocrine loop. An amphiregulin autocrine loop has been suggested to contribute to tumor growth and metastasis. Therefore, we propose to determine the potential role of an amphiregulin autocrine loop in the progression of inflammatory breast cancer. To perform our experiments, we will utilize the SUM149 cell line which was derived from an aggressive inflammatory breast cancer. These cells have an amphiregulin autocrine loop which makes them a good model for our studies. Amphiregulin and other closely related growth factors are synthesized as large membrane associated forms which can be shed from the membrane and released into the microenvironment. Some studies have suggested that these growth factors require shedding in order to interact with the EGFR. This is the reason clinical drugs have been made to prevent the shedding of membrane bound growth factors. However, there is also evidence suggesting that some membrane precursors are biologically active. We found that SUM149 cells have high levels of membrane bound amphiregulin and our data suggest that the membrane bound form may be able to activate the EGFR which could have important implications on cancer progression. Therefore our first aim will be to determine whether membrane bound amphiregulin is biologically active and whether it is required for an amphiregulin autocrine loop. We will test this aim by isolating the membrane bound form of amphiregulin from SUM149 cells and determine how it affects the growth of normal human mammary epithelial cells. We will also inhibit release of The original document contains color images.