Mechanisms and Impact of NRG3 Induction in Bone Metastasis

Without the occurrence of cancer cell dissemination (metastasis), most breast cancer patients would survive following diagnosis and treatment. Alas, cancer cells can disseminate to distant sites long before diagnosis of the primary tumor. Based on clinical investigations, bone is established as the most predominant site of metastasis in breast cancer. Over the years, we started to realize a preferential association of breast cancer subtypes with certain metastatic sites. For instance, hormone receptor- positive (HR+) breast cancer, which represents the most common subtype of breast cancer (65-70%), has a high propensity toward skeletal tissues compared to HR- subtypes (TNBC and HR-/Her2+). Accumulating evidence indicates a key role of bone resident cells (osteoblasts, osteoclasts, and vascular cells) in these processes. Although multiple mechanisms can contribute to these processes, the clinical implications remain limited. Recently, we identified a bone-induced factor (NRG3) that may help switch current paradigms. NRG3 is part of the neuregulin family of ligands that modulate erbb receptors. While the role of Neuregulins is still enigmatic in breast cancer, our preliminary results suggest strong implications in metastasis progression. Here, we will use molecular approaches to (i) determine and functionally characterize the NRG3 regulome induced in the bone microenvironment, (ii) identify the NRG3 signaling using genetic approaches, and (iii) assess the impact of NRG3 depletion on secondary metastasis. Considering the well-established role of Receptor Tyrosine Kinases such as Her2 in stemness, DTC, and metastasis progression, our proposed investigation may uncover novel bone-mediated properties with high therapeutic potential.