Abstract
SummarySolid tumors are often characterized by a hypoxic microenvironment which contributes, through the hypoxia-inducible factor HIF-1, to the invasion-metastasis cascade. Endoplasmic reticulum (ER) stress also leads tumor cells to thrive and spread by inducing a transcriptional and translational program, the Unfolded Protein Response (UPR), aimed at restoring ER homeostasis. We studied ERO1 alpha (henceforth ERO1), a protein disulfide oxidase with the tumor-relevant characteristic of being positively regulated by both ER stress and hypoxia. Analysis of the redox secretome indicated that pro-angiogenic HIF-1 targets, were blunted in ERO1-devoid breast cancer cells under hypoxic conditions. ERO1 deficiency reduced tumor cell migration and lung metastases by impinging on tumor angiogenesis, negatively regulating the upstream ATF4/CHOP branch of the UPR and selectively impeding oxidative folding of angiogenic factors, among which VEGF-A. Thus, ERO1 deficiency acted synergistically with the otherwise feeble curative effects of anti-angiogenic therapy in aggressive breast cancer murine models and it might be exploited to treat cancers with pathological HIF-1-dependent angiogenesis. Furthermore, ERO1 levels are higher in the more aggressive basal breast tumors and correlate inversely with the disease- and metastasis-free interval of breast cancer patients. Thus, taking advantage of our in vitro data on ERO1-regulated gene products we identified a gene set associated with ERO1 expression in basal tumors and related to UPR, hypoxia, and angiogenesis, whose levels might be investigated in patients as a hallmark of tumor aggressiveness and orient those with lower levels toward an effective anti-angiogenic therapy.
Highlights
In the last decade, cancer survival rates have improved thanks to early diagnosis and new anti-cancer drugs
ERO1 expression is higher in basal breast tumor cells
ERO1 RNA levels obtained from Cancer cell line Encyclopedia datasets indicated that ERO1 was highly expressed in several breast cancer cells (Supplementary Fig. 1A), but its level of expression was higher in basal breast cancer cells, which mostly consist of aggressive triple negative breast cancer patients (TNBC)
Summary
Cells were kept in culture for no more than 2 weeks and routinely tested for mycoplasma infection. MDAMB231m cells were selected from parental MDAMB231 (#505366 from ATCC Frederick Cancer Tumor Repository, Maryland, USA) through passages in mice to enhance their tumorigenic and metastatic properties as described in [37]. 410.4 cells (4T1) were provided by Amy M. Fulton (Detroit, Michigan, USA) and E0771 were bought (940001-A from CH3 BioSystems). MDAMB231, MDAMB231m, 4T1 and E0771 cells were infected with a lentiviral vector carrying the coding sequence of the synthetic firefly luciferase gene, luc (Photinus pyralis). Twenty-four hours after infection, cells were selected with is effective in ERO1-devoid breast tumors.
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