A novel strategy targeting TP63 for breast cancer prevention

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Project Summary Abstract Breast cancer is one of the most common cancers affecting women in their lifetime. With more advanced screening methods, the diagnosis of early stages of breast cancer is becoming more common. However, significant gap remains in understanding why some early stage breast cancer progresses to fully malignant cancers. Ductal carcinoma in situ (DCIS) is an early, non-malignant lesion of the breast recognized as a precursor of invasive breast cancer (IDC). It is suggested that a small subpopulation of cancer stem cells in DCIS may play a role contributing to breast cancer progression. Thus, understanding the role of cancer stem cells in the early transition is important for effective cancer prevention. Our recent studies show that vitamin D compounds modify breast cancer cells to less stem-like, more differentiated cells, inhibit mammosphere formation and suppress mammary tumor growth in animals. We hypothesize that cancer stem cells play a role in DCIS transition to IDC, and these small molecules work by targeting key transcription factors to reprogram cancer stem cells and reduce DCIS transition. Cancer stem cells can be reprogrammed by certain key transcription factors. Some of transcription factors, such as Oct4, SOX-2, Klf4 or others, have been known to drive generation and maintenance of cancer stem cells, while TP63, a member of the tumor suppressor gene p53 family, plays a key role in mammary gland development and differentiation. TP63 encodes multiple isoforms, including two major forms, TAp63 and DeltaNp63. Our proposed studies aim to gain novel insights in self-renewal and differentiation process during cancer development with a key focus on TP63 and DeltaNp63. In Aim 1, we will examine the subpopulations of CD44+/CD24-, CD44+/CD24low, and CD44+/CD24hi using cell surface markers, mammosphere formation and stem cell profiles to understand the balancing role of TP63/DeltaNp63 in breast cancer. Mammospheres will be an excellent tool for understanding the cancer stem cell dynamics in vitro and testing small molecules for their potential effects. In Aim 2, we will investigate the role of TP63 and DeltaNp63 in DCIS transition to IDC in vivo. Our study aims to identify cancer preventive agents targeting TP63 in breast cancer. Small molecules that can help reprogram cancer stem cells into specific cell lineages, with reduced proliferation potential, could serve as useful agents in breast cancer prevention. Cancer progression, metastasis, and recurrence are significant problems in managing breast cancer. The present project could provide a novel strategy targeting TP63 for cancer prevention.