(PQ6) Molecular Mechanisms Driving Benign to Malignant Transitions in Breast Cancer

Ductal carcinoma in situ (DCIS) of the breast is a frequently-diagnosed, heterogeneous, pre-neoplastic lesion that can give rise to invasive and metastatic breast cancer (BC). Based on outcome data it is predicted that the majority of DCIS cases would not progress to invasive disease. A better understanding of the mechanism that drive hyperplasia and DCIS disease progression could offer potential targets for prevention of pre-neoplastic development and progression and perhaps reduce over-treatment of benign disease. However, the genetic and signaling changes that can drive invasion and metastasis that occur in a sub-population of DCIS cells, remain undefined. We plan to pursue this gap in knowledge based on our recent findings. We will focus on the tumor suppressor ANCO1 (=ANKRD11) that binds to and regulates the coactivator oncogene, Amplified in Breast cancer 1 (AIB1) that is overexpressed in DCIS. Reduction of AIB1 causes a loss of DCIS bipotential progenitor breast cancer initiating cells (BCIC) and prevents DCIS progression to invasive disease in vivo. AIB1-∆4, is a naturally occurring, more active isoform of AIB1 that lacks the N-terminal domain can drive early stage hyperplasia and DCIS in the mammary gland of transgenic mice. The increased oncogenic potential of AIB1-∆4 is in part due to its lack of repression by ANCO1. Loss of ANCO1 or the gain of ∆4 expression in breast cancer cells leads to changes in recruitment of HDACs and methylated histones to transcription factor complexes and increases transcription of genes that could drive pre-neoplasia. Here we will examine the hypothesis that epigenetic alterations driven by the loss of ANCO1 and/or the gain of AIB1- Δ4 expression results in gene expression changes in pre-neoplastic cells that drive transit to invasive cancer. The aims are: Specific Aim 1: Determine the relative roles of ANCO1, AIB1-FL and -∆4 during development and progression of pre-neoplasia in human breast epithelia Specific Aim 2: Determine genomic regions where ANCO1, AIB1-FL and -∆4 bind and directly modify the epigenome during pre-neoplastic development and progression of breast cancer Specific Aim 3: Determine if alterations in the relative levels of ANC01, AIB1-FL or -∆4 impact the development of pre-neoplasia and progression to invasive cancer in syngeneic mouse models.