| dc.description.abstract | Breast cancer cells frequently disseminate to bone where they proliferate or remain dormant, but the mechanisms controlling entry and exit from quiescence are largely unknown. This dissertation addresses this gap in knowledge by investigating the regulation and downstream signaling of key dormancy factors in the breast tumor microenvironment. Leukemia inhibitory factor receptor (LIFR) maintains bone-disseminated breast tumor cells in a dormant state. Hypoxia, a characteristic of the bone or enlarging tumors, represses LIFR. Our lab previously showed that histone deacetylase (HDAC) inhibitors epigenetically stimulate LIFR and induce dormancy. We sought to determine whether HDAC inhibitors similarly induce dormancy when LIFR is downregulated by the microenvironment. We found that hypoxia epigenetically downregulated LIFR in MCF7 breast cancer cells by modulating repressive and activating histone marks along the promoter. HDAC inhibitors retained their ability to robustly stimulate LIFR repressed by hypoxia or overexpression of parathyroid hormone-related protein (PTHrP), which is elevated in bone-disseminated breast cancer cells to promote osteolysis and bone colonization. PTHrP also promotes dormancy exit in the bone and downregulates numerous pro-dormancy genes, including LIFR, independent of autocrine or paracrine activation of PTHR1. However, PTHrP intracrine actions in breast cancer have not been rigorously examined. We therefore investigated how the biological domains of PTHrP regulate breast tumor progression. In the primary site, stable expression of full-length PTHrP did not impact tumor growth, while deletion of the PTHrP NLS alone dramatically increased tumor growth and proliferation. Surprisingly, deletion of the PTHrP NLS and C-terminus slowed tumor growth, driven by LIFR upregulation, which increased p27 signaling to decrease proliferation. In the bone, PTHrP lacking the NLS or the NLS and C-terminus dramatically increased osteolysis and tumor burden (even greater than full-length PTHrP), suggesting that the NLS drives bone colonization and osteolysis. This work revealed novel mechanisms of breast cancer cell responses to HDAC inhibitors and identifies specific PTHrP domains and downstream pathways that may be targeted to prevent breast tumor progression and improve patient outcomes. | |
