Rho GTPases and their regulators, which are aberrantly expressed in breast cancer, have been implicated as important mediators of extracellular signaling between the epithelial and stromal compartments. Here we sought to elucidate the role of Rho GTPase signaling in epithelial-stromal interactions in the developing mammary gland using two mouse models of mammary gland development that conditionally overexpress different components of Rho GTPase signaling, a Rho GTPase regulator p190B Rho GAP and the Rho GTPase Cdc42, in the mammary epithelium. Previous studies with these mouse models identified stromal alterations reminiscent of tumor associated stroma in conjunction with increased ductal branching and aberrant terminal end bud (TEB) formation in the overexpressing mammary glands. Interestingly, our investigation into the mechanisms of stromal activation in response altered Rho signaling in the epithelium yielded distinct mechanisms for each model.
Stromal activation characterized by increased extracellular matrix (ECM) deposition and remodeling in the p190B overexpressing mammary glands appears to be due in part to altered mechanical signaling between the epithelial and stromal compartments and increased paracrine TGFβ singaling from the p190B overexpressing mammary epithelial cells (MECs). While the Cdc42 overexpressing mammary glands also demonstrated increased levels of ECM proteins and remodeling enzymes, the stroma was additionally characterized by differential activation of the macrophage population. Interestingly, Cdc42 overexpressing mammary glands were found to contain more senescent MECs and an altered secretory profile that appears to be contributing to the pro-inflammatory activation of the adjacent stroma.
Collectively, our studies demonstrate that altered Rho GTPase signaling in the epithelium dramatically alters the adjacent environment through multiple mechanisms involving aberrant epithelial-stromal interactions. Furthermore, our work highlights the need for future studies investigating the involvement of aberrant Rho GTPase signaling in creating a microenvironment permissive to breast cancer development and progression.