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Abstract
Hypoxia within solid tumors presents as a barrier to the effectiveness of cancer treatment. Hypoxia has been implicated in cancer cell resistance to standard therapies used in the clinic to treat breast cancer. Additionally, the treatment resistance mechanisms in cancer cells are exacerbated by oncogenic pathways that enable adaptation to the hypoxia and facilitate therapy resistance. Cancer cells often co-opt signaling pathways essential for embryonic development as a defense against cellular attacks. Hedgehog (Hh) signaling pathway is one of such embryonic development pathways that have been implicated in mitigating cancer growth, metastasis, and resistance to therapy. Hh signaling pathway promotes proliferation, tissue remodeling, patterning, differentiation, and vascularization in normal development. However, abnormal engagement of the Hh pathway in cancer fosters tumor initiation and progression. Dysregulated Hh signaling is also associated with breast cancer progression and metastasis.
In this study, we examine the role of Hh signaling in lethal DNA break repair, adaptation to hypoxia, and crafting of tumor hypoxia. We found that that the zinc-finger transcription factor GLI1, a terminal effector of the Hh pathway, is essential for the repair of ribosomal DNA (rDNA) double-strand breaks (DSBs). Inhibition of GLI1 impairs the global non-homologous end joining (NHEJ) DSB repair pathway. Additionally, we found that inhibiting GLI1 impacts RNA polymerase I activity and cellular viability.
We also report that Hh signaling mitigates tumor hypoxia quantified by radiolabeled tracer, [18F]-fluoromisonidazole (FMISO) positron emission tomography (PET) imaging upon the administration of Vismodegib, a FDA-approved Hh inhibitor in vivo. Furthermore, we uncovered the mechanistic role of Hh in enabling hypoxia adaptation through robust activation of HIF signaling in a VHL-dependent manner. In addition to modulating temporal changes in hypoxia, we found that inhibition of Hh signaling leads to decreased pulmonary metastasis.
Thus, we identified the role of Hh signaling in facilitating defense against genotoxic stress and maneuvering the tumor microenvironment in breast cancer to promote tumor progression and metastasis. Our findings provide a novel insight into targeting Hh signaling in breast cancer clinically to mitigate tumor proliferation, hypoxia, and metastasis.
