Reduced ING1 levels in breast cancer promotes metastasis

Abstract

INhibitor of Growth 1 (ING1) expression is repressed in breast carcinomas, but its role in breast cancer development and metastasis is unknown. ING1 levels were quantified in >500 patient samples using automated quantitative fluorescence immunohistochemistry, and data were analysed for correlations to patient outcome. Effects of altering ING levels were examined in microarrays and metastasis assays in vitro, and in a mouse metastasis model in vivo. ING1 levels were lower in tumors compared to adjacent normal breast tissue and correlated with tumor size (p=0.019) and distant recurrence (p=0.001) in ER- or Her2+ patients. In these patients ING1 predicted disease-specific and distant metastasis-free survival. Transcriptome analysis showed that the pathway most affected by ING1 was breast cancer (p = 0.0008). Decreasing levels of ING1 increased, and increasing levels decreased, migration and invasion of MDA-MB231 cells in vitro. ING1 overexpression also blocked cancer cell metastasis in vivo and eliminated tumor-induced mortality in mouse models. Our data show that ING1 protein levels are downregulated in breast cancer and for the first time, we show that altering their levels regulates metastasis in vitro and in vivo, which indicates that ING1 may have a therapeutic role for inhibiting metastasis of breast cancer.

Predictive Factors of Survival Time of Breast Cancer in Kurdistan Province of Iran between 2006-2014: A Cox Regression Approach

“…Like as previous studies in Iran, median age of breast cancer patients at the time of diagnosis was lower than in developed countries (Korizumi et al, 2010;Khodabakhshi et al, 2011;Thakur et al, 2014).…”

“…For metastasis to occur cancer cells have to attain a specific genotype and epigenotype, which allows them to disseminate from the primary tumor mass, survive, and then proliferate at secondary sites. Breast cancer cells have a distinct epigenomic DNA methylation profile which affects their metastatic potential (Thakur et al, 2014). Recent reports have shown that C-X-C chemokine receptor 4, TNF-α and IL-6 play an important role in metastasis (Tripsianis et al, 2013;Jiyang et al, 2014).…”

Stromal ING1 expression induces a secretory phenotype and correlates with breast cancer patient survival

“…ING1 protein level was measured using quantitative fluorescence immunohistochemistry on the HistoRx AQUA® platform in breast cancer patient samples from the Calgary Tamoxifen cohort as described previously [ 31 ]. The specificity of the ING1 monoclonal antibody used for fluorescence IHC was assessed in HEK293 cells and placental tissue Fig.…”

“…Other members of the ING family, and in particular ING4, have also been reported to be down-regulated in breast cancers with a dominant mutant allele of the ING4 gene promoting tumor growth [ 29 , 30 ]. Recently, we reported that reduced ING1 levels are correlated with increased metastasis in breast cancer patients [ 31 ].…”

Characterization of a murine model of metastatic human non-small cell lung cancer and effect of CXCR4 inhibition on the growth of metastases

“…To obtain qualitative assessments of bone osteolysis caused by metastasis, micro-computed tomography (μCT40, Scanco Medical) was used as previously described [ 32 , 34 ]. To examine angiogenesis of a metastatic site, mouse were terminally perfused with a radio-opaque silicone rubber (Microfil, Flow Tech) to form a radio-opaque vascular cast that can be visualized using μCT as we have previously described [ 35 ].…”