Parathyroid hormone-related protein (PTHrP) is expressed at high levels in breast cancer metastases compared to primary tumours. Although human MCF7 breast cancer cells grow poorly in bones of immune deficient mice, PTHrP overexpression overcomes this dormant phenotype, causing them to grow as osteolytic deposits. By RNAseq and qPCR validation these PTHrP-overexpressing MCF7 cells showed lower expression of genes associated with dormancy, cell growth and invasion compared to vector controls (e.g. AMOT, P4HA1, H2BK, SELENBP1). This is despite early work showing a lack of cyclic AMP (cAMP) response to PTH in MCF7 cells, which would be expected with functioning PTH/PTHrP receptor (PTHR1).

The present work has confirmed the lack of cAMP response in MCF7 cells to full length PTHrP and PTH(1-34) in a wide range of doses, while response to two known activators of adenylyl cyclase was present: calcitonin (100-fold max) and prostaglandin E₂ (PGE₂) (30-fold max). Moreover, whereas both calcitonin and PGE₂ activate cAMP Cre-luciferase transfected into MCF7 cells, PTHrP and PTH had no effect.

PTHR1 mRNA was detectable in MCF7 cells at a low level (30-50-fold lower than in osteoblastic cells with functional PTHR1), as also found in 8 other human breast and murine mammary carcinoma cell lines. However, although PTHrP overexpression in MCF7 cells changed expression levels of many genes (>2500 genes with >1-log₂fold change, p<0.05), PTH1R-responsive cAMP / CREB genes (e.g. NR4A1, NR4A2, RGS2) were poorly represented among those that were increased.

We conclude that MCF7 breast cancer cells have no functional PTHR1. Changes in gene expression seen with PTHrP must therefore result from autocrine or intracrine actions of PTHrP independent of PTHR1, through signals emanating from other domains within the molecule, such as the nuclear localization sequence. These cells therefore offer a model with which to investigate the significance of non-canonical PTHrP actions.