The planar cell polarity (PCP) pathway plays central roles in embryonic development by mediating cellular motility events required for proper tissue structuring. Accumulating evidence suggests that the PCP pathway is exploited by some solid tumors to promote their invasiveness and metastatic potential. Likewise, the epithelial- mesenchymal transition (EMT) is a cellular program widely engaged during development whereby cells lose their epithelial character, including apico-basal polarity and cell-cell interactions, and gain migratory and invasive properties to take on a more mesenchymal stem cell nature. It is well established that solid tumor cells engage EMT in the initiation of metastasis. The purpose of the proposed studies is to examine on a molecular level the link between these two developmental pathways, to discern the degree to which an EMT-PCP axis contributes to the motility and invasiveness of both non-transformed and transformed breast cells, and to unravel a novel molecular mechanism contributing to the suppression of the PCP pathway. We hypothesize that EMT inducers engage the Vangl-dependent planar cell polarity pathway to promote the motility and invasiveness of both non-transformed and transformed breast epithelial cells, and to promote breast cancer metastasis.
Aim 1 will first examine the extent to which EMT induction in breast cells regulates components of the PCP pathway, and then assess whether key components of the PCP pathway are required for EMT- induced breast cell motility and invasiveness. A subset of Aim 1 studies will also attempt to discern whether PCP signaling regulates EMT.
Aim 2 will examine a novel PCP negative regulatory mechanism in detail, exploring the hypothesis that the Vangl-associated E3 ubiquitin ligase Nrdp1 suppresses PCP signaling by mediating the K63 polyubiquitination of Dvl family proteins in breast epithelial and cancer cells.
Aim 3 will examine whether the core PCP component Vangl2 contributes to breast cancer metastasis using genetically- engineered and orthotopic transplant mouse models of basal breast cancer. The successful completion of these studies will uncover a novel connection between two developmental programs that are reactivated by tumor cells in promoting malignancy, and will assess the contribution of this synergistic interaction in promoting breast cancer malignancy.
The proposed studies are aimed at understanding the contribution of a specific developmental pathway to cell motility, particularly to the invasiveness of breast epithelial and breast cancer cells. The successful completion of the studies will contribute to our basic mechanistic understanding of the planar cell polarity pathway in a variety of developmental processes from pubertal mammary development to neural crest migration, and could pave the way for the examination of the aberrant engagement of this pathway by other tumor types.