PRP4K gene regulation in breast cancer and its role in chemotherapy resistance

Breast cancer is the most common cancer found in women yet, even with early diagnosis and treatment, 15-20% will develop recurrent or metastatic disease. Thus, chemotherapy resistance is a major hurdle in curing breast cancer. The taxanes are one of the "front line" chemotherapy agents used alone or in combination with the anthracyclines to treat breast cancer. Patients with breast cancers that express the human epidermal growth factor receptor 2 (HER2/ERBB2) gene appear to show the greatest benefit from taxanes. However, HER2 positive cancers are also aggressive and the reason for their taxane sensitivity remains unclear. Unfortunately, breast cancer cells are often resistant to these drugs and their side-effects can cause significant suffering. Therefore, a better understanding of both the hallmarks and mechanisms of taxane-resistance is essential in developing therapies to battle resistance in breast cancer, and to ensure that only patients who will benefit from taxane therapy are given these drugs.This proposal will focus on characterizing a new biological marker of taxane sensitivity that is regulated by HER2 called PRP4K, an exciting finding that could explain why HER2+ cancers are susceptible to taxanes. Through these studies we will develop a better understanding of the mechanisms by which breast cancer cells develop taxane resistance, and the role that PRP4K plays in this process. The ultimate goal being to develop therapies that can target taxane-resistant cancer cells and improve the overall outcome for breast cancer patients. AIM 1To determine the mechanism(s) by which HER2/ERBB2 signalling regulates PRP4K levels in breast cancer, a) transcriptionally, and/or b) post-transcriptionally.AIM 2To determine the relationship between PRP4 kinase, autophagy and taxane resistance.