Stanniocalcin 2 Expression is Regulated by Hormone Signalling and Negatively Affects Breast Cancer Cell Viability in Vitro

Stanniocalcin 1 (STC1) and STC2 are secreted, homodimeric glycoproteins that share 30% amino acid sequence identity. Breast tumour gene profiling studies have demonstrated significantly upregulated STC2 expression in hormone-responsive positive breast tumours; therefore, the purpose of this study was to investigate STC2 hormonal regulation and function in breast cancer cells. Here we report that STC2 is expressed in a number of human breast cancer cell lines, regardless of their oestrogen (E(2)) and progesterone (P4) receptor status, and its expression is readily detectable in human and mouse mammary gland tumours. Besides E(2), retinoic acid (RA) and P4 play an important role in the regulation of STC2 expression, not only in MCF-7 but also in other breast cancer and non-breast cell lines. The expression of the related hormone, STC1, is not affected by the above hormones in breast and endometrial cancer cell lines implying a fundamental difference in regulation in cancer cell lines. The induction of STC2 expression by E(2) and RA occurs at the transcriptional level but through intermediary transcription factors. The STC2 proximal promoter region is not responsible for hormonal induction, but exhibits a high basal transcriptional activity. Constitutive STC2 expression in human breast cancer cell lines resulted in significant impairment of cell growth, migration and cell viability after serum withdrawal. In conclusion, STC2 is a downstream target of E(2), P4 and RA signalling pathways. In hormone receptor negative cell lines it can function in a paracrine/autocrine fashion to reduce cell proliferation.