Abstract
The relationship between oestrogen (E2) 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 E2 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 E2. However, only the growth of MCF 7/5–23 cells was stimulated (266%) by IGF-1. A combination of E2 and IGF-1 significantly enhanced MCF 7/5–21 and 7/5–23 cell growth (581% and 695%, respectively). E2-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 E2-induced expression of IGF-2 using RT-PCR was demonstrated in the MCF 7/5–23 cells. These experiments indicate that E2 may sensitize tamoxifen-resistant MCF 7/5–23 cells to the growth stimulatory actions of IGF-2 via up-regulation of the IGF-1R and describes a cell-survival mechanism that may manifest itself as tamoxifen resistance. © 1999 Cancer Research Campaign
Highlights
Oestrogens (E2) stimulate the proliferation of human breast cancer cells predominantly via the oestrogen receptor (ER)
insulin-like growth factor (IGF)-1 is a mitogen for human breast cancer cells in vitro (Lippman, 1985), especially in the presence of E2, and acts primarily via a specific cell surface glycoprotein receptor known as the type 1 IGF receptor (IGF-1R; Steele-Perkins et al, 1988)
The PCR cycling parameters were determined from preliminary experiments where we demonstrated that amplification of both IGF-2 and H3.3 levels was in the exponential phase of PCR at 35 cycles for the concentrations of template that were used
Summary
Oestrogens (E2) stimulate the proliferation of human breast cancer cells predominantly via the oestrogen receptor (ER). The clinical effectiveness of antioestrogens such as tamoxifen in ER+ cells is occasionally limited by intrinsic resistance or, more commonly, the acquisition of resistance. The mechanisms underlying the development of anti-oestrogen insensitivity remain elusive, as it is recognized that tamoxifen resistance is generally not associated with the loss or abnormal function of the ER (Encarnacion and Fuqua, 1994). An alternative mechanism may be the progression of breast tumours to a hormone-independent proliferative state whereby growth factors act as the principal mitogens (Dickson et al, 1993). IGF-1 is a mitogen for human breast cancer cells in vitro (Lippman, 1985), especially in the presence of E2, and acts primarily via a specific cell surface glycoprotein receptor known as the type 1 IGF receptor (IGF-1R; Steele-Perkins et al, 1988)
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