Altered expression of the IGF-1 receptor in a tamoxifen-resistant human breast cancer cell line

Abstract

SummaryThe relationship between oestrogen (E 2 ) and insulin-like growth factor-one (IGF-1) was examined in both tamoxifen-sensitive (MCF 7/5-21) and tamoxifen-resistant (MCF 7/5-23) subclones of the MCF 7 cell line. Both subclones were grown in defined, serum-free (SF) medium over a period of 7 days with the addition of E 2 or IGF-1 or a combination of both agents. Growth of both MCF 7/5-21 and 7/5-23 cells was stimulated (245% and 350%, respectively) by E 2 . However, only the growth of MCF 7/5-23 cells was stimulated (266%) by IGF-1. A combination of E 2 and IGF-1 significantly enhanced MCF 7/5-21 and 7/5-23 cell growth (581% and 695%, respectively). E 2 -induced IGF-1 receptor (IGF-1R) levels (as measured by 125 I-IGF-1 binding and Northern analyses) in only MCF 7/5-23 cells. This effect was partially inhibited by tamoxifen. In medium containing serum, the growth of only the MCF 7/5-23 cells was significantly inhibited by the IGF-1R monoclonal antibody, αIR-3. The detection of E 2 -induced expression of IGF-2 using RT-PCR was demonstrated in the MCF 7/5-23 cells. These experiments indicate that E 2 may sensitize tamoxifen-resistant MCF 7/5-23 cells to the growth stimulatory actions of IGF-2 via upregulation of the IGF-1R and describes a cell-survival mechanism that may manifest itself as tamoxifen resistance.

Insulin-like Growth Factor Receptor Levels Are Regulated by Cell Density and by Long Term Estrogen Deprivation in MCF7 Human Breast Cancer Cells

“…6). Although IGFR levels have been reported to be dependent on estrogen (9,14), this has not been a universal finding in all reports (41). Although results presented here suggest that discrepancies may be explained by lack of consideration to cell density in assays, another explanation could lie with the different culture conditions used.…”

“…However, upon long term removal of estrogen from the culture medium, the cells gradually adapt, developing an ability to grow without estrogen until they can eventually grow at the same rate as they had done previously only in the presence of estrogen (38 -40). Similar adaptive processes enable the cells to escape from growth inhibition imposed by the anti-estrogens tamoxifen (41) and ICI 182,780 (42) or by retinoic acid (43). The molecular basis for this growth adaptation remains unknown, but recent work has shown that development of estrogen hypersensitivity resulting from up-regulation of ER and increased estrogen-regulated gene expression may be involved (44).…”

Reversibility and recurrence of IGF-IR-induced mammary tumors

“…Also, IGF-IR is frequently overexpressed in breast cancer (Surmacz, 2000) with tyrosine kinase activity of IGF-IR increased as much as 40-fold in tumor cells compared with normal breast tissue (Resnik et al, 1998). Upregulation of IGF-IR signaling has also been implicated in mediating resistance of breast cancer cells to chemotherapeutic agents, radiation, and targeted therapies such as Tamoxifen (Parisot et al, 1999) and Herceptin (Lu et al, 2001).…”

Epidermal growth factor receptor/HER2/insulin-like growth factor receptor signalling and oestrogen receptor activity in clinical breast cancer

“…While controversial, additional model systems tentatively implicate IGF-IR signalling in tamoxifen resistance. Growth of the tamoxifen-resistant MCF-7/ 5-23 cell line was significantly inhibited by the IGF-1R antibody aIR-3 (Parisot et al 1999), while further acquired tamoxifen-resistant models have been described where proliferation is dependent on IGF signalling (Wiseman et al 1993). There thus appears to be emerging evidence of a role for IGF-1R in acquired tamoxifen-resistant as well as -responsive cells.…”