Head and neck squamous cell carcinoma (HNSCC) is the 6th most common type of cancer in the western hemisphere with a five-year survival rate of only 50% for patients with a localized tumor, which decreases significantly to as low as 5% for those patients with tumors that have metastasized to distant sites of the body. It has been found that both mutant p53 and epidermal growth factor receptor (EGFR) signaling pathways function to increase the expression of CXCL5, which has been identified as a key mediator in the process of tumor metastasis. Previous data from our lab suggested that the p53 homolog, p63, may function as a negative regulator of CXCL5 and that mutant p53 may inhibit this molecule to elevate CXCL5 expression levels. In the current study we utilized an model system in which the H179L p53 mutant was expressed in HN4 cells to investigate the hypothesis that mutant p53 enhances expression of CXCL5 by both interfering with p63 function and cooperating with EGFR/EPS8 signaling, leading to increased cell proliferation and motility. The results of the current study indicate a role for mutant p53 in head and neck squamous cell carcinoma proliferation, migration and tumorigenicity, possibly through enhancement of CXCL5 expression. We were able to show that mutant p53 expression caused an increase in the expression of this chemokine in addition to increasing proliferation and migration of the cells compared to the vector control. Additionally, we showed that p63 protein is a negative regulator of CXCL5 that is downregulated in the cells expressing mutant p53, which suggests that through direct interaction, mutant p53 may function to inhibit p63 function as well as target it for degradation. These results support the hypothesis that GOF mutant p53 enhances expression of CXCL5 by interfering with p63 function in cancer cells. The results of the current study results also showed that upon treatment with EGF, HN4 cells expressing mutant p53 express elevated levels of CXCL5; and that the mutant p53-expressing HN4 cells cooperate with EGFR/EPS8 signaling to further deregulate chemokine expression. These data taken together suggest there are complex interactions taking place between mutant p53, p63, EGFR signaling, and CXCL5 to regulate the biological processes that promote tumor progression that could lead to metastasis. Additional studies are needed to further elucidate the molecules involved in the mutant p53 mechanism that promotes tumorigenesis.