Biglycan and reduced glycolysis are associated with breast cancer cell dormancy in the brain

Abstract

Exit of quiescent disseminated cancer cells from dormancy is thought to be responsible for metastatic relapse and a better understanding of dormancy could pave the way for novel therapeutic approaches. We used an in vivo model of triple negative breast cancer brain metastasis to identify differences in transcriptional profiles between dormant and proliferating cancer cells in the brain. BGN gene, encoding a small proteoglycan biglycan, was strongly upregulated in dormant cancer cells in vivo. BGN expression was significantly downregulated in patient brain metastases as compared to the matched primary breast tumors and BGN overexpression in cancer cells inhibited their growth in vitro and in vivo. Dormant cancer cells were further characterized by a reduced expression of glycolysis genes in vivo, and inhibition of glycolysis in vitro resulted in a reversible growth arrest reminiscent of dormancy. Our study identified mechanisms that could be targeted to induce/maintain cancer dormancy and thereby prevent metastatic relapse.

Analyses of hypoxia-related risk factors and clinical relevance in breast cancer

“…Among the protective factors in our model, FOS is a proto-oncogene of the activator protein-1 (AP-1) transcription factor subunit ( 40 ) and participates in a variety of cellular functions and apoptotic cell death, including regulating the development and progression of BRCA ( 41 , 42 ), and its overexpression attenuates the malignant phenotypes of BRCA cells according to the lines of evidence from in silico and in vitro studies ( 43 ). The protein encoded by BGN (biglycan) was proven to induce BRCA cell normalization ( 44 ) and inhibit the initial outgrowth of brain metastases in BRCA patients ( 45 ). EGFR is generally considered to stimulate cell proliferation and promote cancer cell survival ( 46 ).…”

Dormant cancer cells and polyploid giant cancer cells: The roots of cancer recurrence and metastasis

“…Glypican‐3 can induce tumour dormancy through the activation of p38 MAPK signalling pathway 81 . In cancer cells, the quiescence program of dormancy is induced by p38/MAPK activation, 81 extracellular signal‐regulated kinase (ERK) 101 and phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT) inactivation, 102 as well as by decreasing glycolysis 103 and glucose uptake 104,105 . A high ratio of p38/ERK induces cells to enter dormancy, whereas a high ratio of ERK/p38 induces dormant cells to grow and proliferate 5,101,106 .…”