1 Project Abstract: Although the number of people developing breast cancer (BC) each year has remained the 2 same, 5-year survival rates for late stage disease are still an abysmal 17-26%. However, one positive indicator 3 of survival is how well the patient’s immune system is able to recognize the tumor and attack it, using immune 4 cells like tumor-associated macrophages (TAMs). Basal-like, triple negative BC (TNBC) is a uniquely deadly 5 type of BC and accounts for about 20% of BC cases. TNBC does not grow because of hormone and growth 6 factors, but instead frequently activates other pro-growth signals like the expression of secreted WNT proteins 7 that act as messengers to nearby cells. In addition, TNBC is more likely to manipulate the immune system into 8 a tumor-promoting mechanism instead of a tumor-fighting one. This is accomplished by inducing TAMs to 9 program into a tumor-promoting M2 state, which helps create an environment for tumors to thrive by promoting 10 blood vessel growth, instead of a tumor-fighting M1 state. We have identified the DEK protein as a key driver of 11 BC growth and disease progression. DEK is highly expressed – meaning too much protein is made compared 12 to normal cells - in about 60% of all breast cancers, especially TNBC. DEK is over-expressed in all types of 13 cancer studied so far, meaning that understanding how DEK functions to promote cancer growth and disease 14 progression could have a far-reaching impact in understanding cancer biology. We have previously used cultured 15 cells to discover that DEK promotes the proliferation of cancer cells by increasing the expression of several WNT 16 genes that then get secreted to act on neighboring cells, but have not yet investigated this in animal models. 17 Interestingly, our preliminary data suggest that the WNT proteins produced by DEK-expressing cancer cells may 18 signal to TAMs to enter an M2-like state to further promote tumor growth. We hypothesize that DEK over- 19 expression in BC promotes tumor formation via elevated WNT expression, which acts both on neighboring 20 epithelial cells and on macrophages. We will use three-dimensional cell culture of human cells, patient samples, 21 and new mouse models of BC to test this hypothesis. In Aim 1, we will use a new DEK over-expression model 22 in the mammary epithelium of mice to Determine when and how DEK promotes tumor growth. We will also 23 determine the necessity for continued DEK expression to maintain tumor growth, which will inform the feasibility 24 of creating DEK-targeting therapies in the future. Aim 2 will investigate how important WNT proteins are for the 25 ability of DEK to promote tumor growth and progression. Finally, Aim 3 will examine how DEK and WNT proteins 26 work together to induce TAMs to enter the tumor-promoting M2 s...