Expression of insulin-like growth factor binding protein-3(IGFBP-3) is down regulated in breast cancer compared to normal breast tissue
K McCarthy1, CA Laban1, SA Bustin2, BW Ogunkolade1, R Carpenter3 & PJ Jenkins1
Background: Recent studies have suggested that an increased level of serum IGF-1 and a decreased level of IGFBP-3 may be associated with an increased risk of developing subsequent breast cancer. However, it is uncertain whether these effects are mediated solely by endocrine actions or whether local effects might also be important. We have previously demonstrated IGF-1 mRNA to be universally expressed in normal breast tissue but in only 50% of cancers. The expression of IGFBP-3, which both regulates the actions of IGF-1 and exerts independent effects on cell apoptosis, is unknown.
Aims: (i) To quantify the expression of IGFBP-3 in normal and malignant breast tissue. (ii) To correlate this with expression of IGF-1 and other tumour associated genes.
Methods: Total RNA was extracted from 38 paired samples of normal and malignant breast tissue. Local Ethical Committee Approval was obtained. mRNA transcription was quantified using a real time, hydrolysis probe-dependant RT-PCR assay ('Taqman') and expressed as logcopy number per microgram total RNA.
Results: IGFBP-3 was expressed in all samples. However, its expression was down regulated in tumour compared to normal tissue. Median copy number (range):6.4x106(1.8x105 to 6.2x107)versus 1.1x107 (2.6x105 to 1.8x108) respectively; p<0.05. Furthermore, expression was decreased in IGF-1 negative compared to IGF-1 positive cancers: median copy number (range): 4.2x106(1.8x105 to 6.2x107) versus 9.4x106 (1.6x106 to 5.2x107) respectively; p<0.04. There was no significant correlation between IGFBP-3 expression and that of growth hormone, c-myc, Cox-2 or PCNA. There was, however, a significant positive correlation between IGF-1 and IGFBP3 mRNA levels in normal (R=0.39, p<0.01) and cancers(R=0.49, p<0.002), which was strengthened with IGF-1 positive cancers (R = 0.52, p<0.01).
Conclusions: The universal expression of the pro-apoptotic IGFBP3 but down regulation in cancers suggests a role for it in normal breast tissue homeostasis. However, its expression in IGF-1 negative cancers is further support for IGF-1 independent effects.