Abstract
Simple SummaryBreast cancer patients are frequently complicated by bone metastasis, which deteriorates their life expectancy. Bone metastasis is treated with the drugs targeting osteoclast activation, which is mostly observed at the metastasis sites. However, these drugs cannot directly inhibit cancer cell growth and therefore, a novel therapeutic strategy is required to impede cancer cell proliferation at bone metastasis sites. Here, we proved that a transcription factor, NFE2, was expressed selectively in breast cancer cells at bone metastasis sites and contributed crucially to their enhanced proliferation therein, by activating Wnt pathway. Thus, NFE2 can be a novel molecular target to treat breast cancer bone metastasis.Patients with triple negative breast cancer (TNBC) is frequently complicated by bone metastasis, which deteriorates the life expectancy of this patient cohort. In order to develop a novel type of therapy for bone metastasis, we established 4T1.3 clone with a high capacity to metastasize to bone after orthotopic injection, from a murine TNBC cell line, 4T1.0. To elucidate the molecular mechanism underlying a high growth ability of 4T1.3 in a bone cavity, we searched for a novel candidate molecule with a focus on a transcription factor whose expression was selectively enhanced in a bone cavity. Comprehensive gene expression analysis detected enhanced Nfe2 mRNA expression in 4T1.3 grown in a bone cavity, compared with in vitro culture conditions. Moreover, Nfe2 gene transduction into 4T1.0 cells enhanced their capability to form intraosseous tumors. Moreover, Nfe2 shRNA treatment reduced tumor formation arising from intraosseous injection of 4T1.3 clone as well as another mouse TNBC-derived TS/A.3 clone with an augmented intraosseous tumor formation ability. Furthermore, NFE2 expression was associated with in vitro growth advantages of these TNBC cell lines under hypoxic condition, which mimics the bone microenvironment, as well as Wnt pathway activation. These observations suggest that NFE2 can potentially contribute to breast cancer cell survival in the bone microenvironment.
Highlights
Breast cancer is the most prevalent cancer in females with 280,000 new cases annually in the UnitedStates alone [1]
We provided evidence to indicate that Nfe2, a transcription factor involved in normal and malignant hematopoiesis [13,14,15,16,17], could provide breast cancer cells with an advantage to grow efficiently in a bone cavity, thereby accelerating breast cancer bone metastasis
The injection of either clone resulted in similar mRNA expression levels of Rank, Rank ligand (Rankl), and osteoprotegerin (Opg) (Figure 1f), which are presumed to be involved in osteoclastogenesis
Summary
Breast cancer is the most prevalent cancer in females with 280,000 new cases annually in the UnitedStates alone [1]. Bone metastasis is frequently treated with bisphosphonates and/or denosumab, a monoclonal antibody against the receptor activator of NF-κB (RANK) ligand, to inhibit osteoclast activation, thereby controlling bone metastasis [5]. These drugs have disease-modifying effects but are mostly palliative due to their indirect effects on intraosseous cancer cells [5]. It is, necessary to develop a novel type of agents, which can inhibit the growth of cancer cells in a bone cavity, based on the understanding the molecular and cellular mechanisms underlying bone metastasis
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