Type I insulin-like growth factor receptor gene expression in normal human breast tissue treated with oestrogen and progesterone

Abstract

Summary The epithelial proliferation of normal human breast tissue xenografts implanted into athymic nude mice is significantly increased from basal levels by oestradiol (E2), but not progesterone (Pg) treatment at serum concentrations similar to those observed in the luteal phase of the human menstrual cycle. Type IGF receptor (IGFR-1) mRNA and protein have been shown to be up-regulated by E2 in MCF-7 breast cancer cells in vitro in which IGF-I and E2 act synergistically to stimulate proliferation. We have investigated the expression of the IGFR-I mRNA in normal human breast xenografts treated with or without E2 or Pg alone and in combination. Northern analysis of 20 gg of RNA extracted from the breast xenograft samples showed no hybridization with 32P-labelled IGFR-I probe, although an 11-kb species of IGFR-I mRNA could be seen when 20 .g of RNA extracted from either MCF-7 breast cancer cells or human breast carcinomas was examined in this way. In order to analyse the expression of IGFR-1 mRNA in breast xenografts, a quantitative reverse transcription -polymerase chain reaction (RT-PCR) was employed in which RNA loading, reverse transcription and PCR efficiencies were internally controlled. The data indicate that the IGFR-I mRNA is up-regulated by two to threefold compared with untreated levels by 7 and 14 days E2 treatment. In contrast, 7 or 14 days Pg treatment downregulates the receptor mRNA to approximately half that of untreated levels, whereas combination E2 and Pg treatment produced a twofold increase in IGFR-I mRNA levels compared with untreated tissue. The results are consistent with the suggestion that E2 may act to stimulate proliferation indirectly via a paracrine mechanism involving IGFs in normal as well as malignant human breast epithelial cells.

Breast cancer: further metabolic-endocrine risk markers?

“…A recent report of upregulation of type 1 IGF receptor by oestradiol in normal human mammary tissue xenografts in nude mice (Clarke et al, 1997) provides in vivo evidence that oestradiol may stimulate proliferation in human mammary epithelium by a paracrine mechanism involving IGF1. In addition, circulating IGF1 may exert an endocrine effect on breast tissue, and interaction with oestrogen may promote breast cancer progression after malignant transformation.…”

“…It has been suggested that oestrogen stimulates the proliferation of breast cancer cells by regulating pathways distal to the IGFR (Westley and May, 1994). A recent study on normal human breast tissue xenografts in nude mice (Clarke et al, 1997) showed that oestradiol caused upregulation of the type 1 IGF receptor.…”

“…ER expression in normal breast tissue is correlated with its proliferative activity and it has been postulated that the mitogenic activity of insulin-like growth factor 1 (IGF1) might interact with that of oestradiol in promoting breast cancer development after the initiation of carcinogenesis (Clarke et al, 1997). It is useful to summarize recent studies attempting to correlate measurements of ER and IGF1 with those of IGFI receptor (IGFR) and binding proteins (IGFBPs) in human breast cancer and in normal mammary epithelium.…”

Role of insulin-like growth factor 1 receptor signalling in cancer

“…The promoter of IGF-1R is CG-rich and lacks TATA and CCAAT elements (LeRoith et al, 1995b), but has elements found in housekeeping genes, containing regulatory elements characteristic for highly regulated genes (Werner et al, 1991). The IGF-1R promoter exhibits a high basal transcriptional activity, and is under physiological control of nutritional factors (Olchovsky et al, 1993), hormonal stimulation (Clarke et al, 1997) and the developmental stage (Bondy et al, 1992). Its expression is altered in certain diseases, including cancer (LeRoith et al, 1995a;Baserga et al, 1997).…”

Teenage obesity in relation to breast cancer risk

“…Its concentration is higher in cancer cells than in normal breast tissue or benign tumours, and the IGF1 receptor interacts with the oestrogen receptor in stimulating proliferative activity both in cancer cells 81 and in explants of normal mammary epithelium. 82 IGF bioactivity in mammary tissue is in¯uenced by autocrine and paracrine secretion of IGF1 and IGF11, by circulating IGF1 levels and by the levels of IGFbinding proteins (IGFBPs) and IGFBP proteases. 83 IGF1 circulates as a complex, bound to IGFBPs, of which six appear to have a major role in maintaining the pool of bound IGF1 which responds to metabolic demands.…”