Involvement of a Transcription factor, Nfe2, in Breast Cancer Metastasis to Bone

Abstract

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.

Integrated profiling of human pancreatic cancer organoids reveals chromatin accessibility features associated with drug sensitivity

“…In the newly discovered glycomet subtype, we found many enriched TFs such as NFE2, MAFK and PAX8, which have been demonstrated to played critical roles in other aggressive solid cancers, facilitating a deeper understanding for this subtype. Recent studies proposed that overexpression of NFE2 could significantly enhance the metastasis capability of triple-negative breast cancer by mimicking the bone microenvironment and activating Wnt pathway 39 . Similarly, MAFK was also reported to promote the progression of triple-negative breast cancer, in which MAFK notably induced epithelial-mesenchymal transition (EMT) and tumor invasion by regulating the targeted gene GPNMB 40 .…”

Crucial contribution of GPR56/ADGRG1, expressed by breast cancer cells, to bone metastasis formation

“…Deletion of Gpr56/Adgrg1 , but not that of other receptor genes, significantly reduced tumor formation upon intraosseous injection (Figure 1C and Figure S3 ). In order to validate the reproducibility from another mouse TNBC cell line, TS/A, we additionally obtained TS/A.3 clone, which exhibited no differences in the growth rates at the primary sites but enhanced tumor formation upon intraosseous injection, compared with its parental clone 11 , 12 (Figure S4 A). TS/A.3 exhibited enhanced GPR56/ADGRG1 expression at tumor foci arising from the intraosseous injection, but not under in vitro culture conditions (Figure S4 B).…”

Extracellular Vesicles in Tumors: A Potential Mediator of Bone Metastasis

“…Breast cancer patients develop tumor metastasis during the advanced stages of disease. Bone tissue is one of the most common sites for metastases in patients with advanced breast cancer, and the metastatic ratio is much higher than that of the liver, lung, and kidney ( Park et al, 2020 ; Zhang D. et al, 2020 ). Breast cancer metastasis to bones not only affects patient quality of life but also results in anemia, fractures, paraplegia, hypercalcemia, pain, cachexia, and increased mortality ( Fico and Santamaria-Martinez, 2020 ).…”

“…Multiple bone growth factors are activated and released during bone resorption and remodeling, which provide an appropriate microenvironment for tumor cell growth, invasion, and metastasis ( Zhao Z. et al, 2020 ). Once breast cancer cells have migrated to bone, the unique bone microenvironment could help to exchange biological information from the tumor cells to osteoblasts and osteoclasts, breaking the balance between osteolysis or osteogenesis during bone remodeling, which further results in fractures and pain and finally leads to death ( Zhang D. et al, 2020 ; Pang et al, 2021 ). Although the tumors can be excised in clinical settings, tumor cells have often already spread and metastasized to bone, resulting in osteolytic lesions.…”