Stanniocalcin (STC) is a secreted glycoprotein first discovered in bony fish. Two homologues, STC1 and STC2, have been identified in mammals and both are expressed in a variety of tissues including kidney, bone, mammary gland, testes and ovary. There is now a considerable body of evidence to indicate that STCs have a role in cancer, and several studies have indicated that their expression may be useful for cancer diagnosis and/or classification. To investigate the role of STCs in breast cancer, we examined STC1/2 expression using quantitative RT-PCR on a series of isogenic mammary tumour lines with varying degrees of metastatic capacity when injected into Balb/c mice. We found that high STC1 expression was associated with the highly metastatic ‘triple negative’ (ER-/PR-/Her2-) 4T1.2 and 4T.13 lines, with very low levels in the 67NR (non-metastatic) and 66cl4 (weakly metastatic) lines. This was confirmed with subsequent northern and western blot analysis. STC2 expression is not altered in these cell lines.
To explore the function of STC1, we down-regulated its expression using lentiviral vectors encoding STC1 shRNA. Cells transduced with non-targeting shRNA were used as a negative control. These cells were then injected into the mammary gland of female Balb/c mice and mammary tumour growth was monitored. Cells with STC1 down-regulation were found to develop primary mammary tumours at a much slower rate than control cells. In vitro experiments on cell migration and invasiveness through Matrigel associated STC1 expression with a more migratory and invasive phenotype.
Bioinformatic analysis of human breast cancer data sets indicated that STC1 is a metastasis-associated gene within the poor prognosis triple negative subtype. Our preclinical study indicates that STC1 has a positive role in primary breast tumour growth and possibly in metastasis as well, although this still needs to be clearly demonstrated.