Endocrine Abstracts (2006) 11 P477

Insulin-like growth factor-i signalling in tamoxifen sensitive and tamoxifen resistant breast cancer cells

CJ McVittie1, S Khalaf2, W Ogunkolade2, R Carpenter1, SA Bustin3 & PJ Jenkins2


1Department of Breast Surgery, Barts Hospital, London, United Kingdom; 2Department of Endocrinology, Barts and the London, London, United Kingdom; 3Department of Academic Surgery, Barts and the London, London, United Kingdom.


Background: Due to its cross-talk with estrogen receptor (ER) signalling, increased IGF-I signalling through the IGF-I receptor (IGF-IR) has been postulated as an important factor in the development of tamoxifen resistance in breast cancer.

Aims: To investigate the importance of IGF-I signalling in tamoxifen resistant (TR) and wild-type (WT) MCF-7 breast cancer cells by (i) assessing cell proliferation in response to IGF-I and tamoxifen and (ii) using small interfering RNA (siRNA) to silence IGF-IR expression.

Methods: We have previously established a TR cell line from a parent MCF-7 cell line. (i) WT & TR cells were cultured in media ±50 ng/ml IGF-I ±10−7 M 4-OH tamoxifen. Cell proliferation was assessed every 24 hours using the MTS assay. (ii) WT & TR cells were transfected with 200 nM IGF-IR-specific siRNA for 15 days. Cell proliferation was assessed every 3 days. Previous optimisation has verified >90% reduction in IGF-IR levels in siRNA transfected cells.

Results: (i) WT cell proliferation showed a significant increase when cultured with IGF-I and decrease when cultured with tamoxifen. In contrast TR cells showed no significant response to IGF-I or tamoxifen (mean cell number ± S.D. expressed as % of media only).

Table 1
WT + IGF-IWT + TamTR + IGF-ITR + Tam
24 hrs146.3±16*65.3± 6*97.5±1389.9±7
48 hrs206.9±11*61.1± 3*110.2±8100.1±3
72 hrs259.3±28*56.7± 3*103.7±8100.4±9

(ii) Silencing of the IGF-IR caused a rapid decline in WT cell number but significantly less effect was seen in the TR cells (47.2±10% vs. 93.4±7% at day 3**, 23.8±8% vs. 59.6±9% at day 9** and 14.0±5% vs. 49.2±7% at day 15**). (*P<0.0001; **P<0.0001).

Conclusions: In contrast to expectation, development of tamoxifen resistance appears to also involve resistance to the effects of IGF-I and IGF-IR signalling. This may reflect the close interaction between the ER and IGF-IR signalling pathways.

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