Promotion of Tumor-Initiating Cells in Primary and Recurrent Breast Tumors.

摘要

Breast tumors, like other solid tumors, contain a subset of cells known as tumor initiating cells (TICs). TICs are important in tumor initiation and recurrence, metastasis, and are resistant to radiation and chemotherapy. Our data and work published by others indicate that the transcription factor NF- B is likely to be important in the generation and maintenance of breast TICs. A major problem in breast cancer therapy is the issue of residual disease where therapy-resistant cancer cells remain dormant only to drive tumor recurrence years later. Here we propose to explore mechanisms whereby NF- B is activated in breast cancer TICs and recurrent experimental tumors and the roles that IKK/NF- B play in this process. Our hypothesis is that the IKK/NF- B pathway is essential for the development and/or maintenance of breast cancer TICs, potentially through the promotion of EMT and the regulation of expression of genes which confer stemness. We hypothesize that inhibition of IKK/NF- B will reduce or eliminate breast camcer TICs, blocking tumorigenesis. Furthermore, we hypothesize that the activation of NF- B is an important component in the generation of recurrent diseases derived from residual disease. The Aims are to: (i) Explore the mechanistic roles for IKK/NF- B in promoting basal-like and Her2+ tumor initiating cells. (ii) Test IKK inhibitors and mTOR inhibitors for effects on tumor growth and TIC phenotypes, (iii) Determine the requirement for the NF- B, TGF and mTOR pathways in promoting the survival and recurrence of residual cancer cells.