Frances S. KENNY1, Julia M.W. GEE3, Robert I. NICHOLSON3, Ian O. ELLIS2, Teresa M. MORRIS4, Susan A. WATSON4,
Richard P. BRYCE5 and John F.R. ROBERTSON1*
1 Professorial Unit of Surgery, City Hospital, Nottingham, United Kingdom
2 Department of Histopathology, City Hospital, Nottingham, United Kingdom
3 Tenovus Cancer Research Centre, University of Wales College of Medicine, Cardiff, United Kingdom
4 Cancer Studies Unit, Department of Surgery, Queen’s Medical Centre, Nottingham, United Kingdom
5 Scotia Pharmaceuticals, Stirling, United Kingdom
Gamma linolenic acid (GLA) possesses a number of selective
anti-tumour properties including modulation of steroid
receptor structure and function. We have investigated the
effect of dietary GLAon the growth, oestrogen receptor (ER)
expression and fatty acid profile of ER1ve human breast
cancer xenografts. Experimental diets A, B, C, D were commenced
after subcutaneous implantation of 40 female nude
mice with the MCF-7 B1M cell line (Group A 5 control diet:
B 5 control diet 1 GLA supplement: C 5 control diet 1
tamoxifen: D 5 control diet 1 GLA 1 tamoxifen; 10 mice/
group). The mice were terminated when tumour cross-sectional
area reached 250 mm2. ER H-scores were assessed by
immunohistochemical assay and fatty acid profiles by gasliquid
chromatography of termination tumour samples.
Groups C and D displayed significantly slower tumour
growth (p5.0002, p5.0006) with trend for slower growth in
B (p 5 .065) compared to control Group A. ER was significantly
reduced in all groups compared to A (p < .0001) with
Group D (combined therapy) displaying markedly lower ER
expression than with either therapy alone (p5.0002). There
were significantly raised levels of tumour GLA and metabolites
in the two groups (B and D) receiving GLA (p < .0001).
This xenograft model of ER1ve breast cancer has demonstrated
significantly lower tumour ER expression in those
groups receiving GLA, an effect which appears to be additive
to the reduced ER expression resulting from tamoxifen
alone. The effects of GLA on ER function and the possibility
of synergistic inhibitory action of GLA with tamoxifen via
enhanced down-regulation of the ER pathway require further
investigation.
© 2001 Wiley-Liss, Inc.
Key words: gamma linolenic acid; tamoxifen; oestrogen receptor;
endocrine response; breast cancer
Gamma linolenic acid (GLA) is a Gamma linolenic acid (GLA) is a member of the n-6 family of
essential polyunsaturated fatty acids (EFAs) found in evening
primrose and borage oils. GLA is well established as an effective
treatment for benign cyclical mastalgia where the mechanism of
action is thought to involve attenuation of breast hormone receptor
sensitivity to circulating oestrogens.1 More recently GLA and
other n-6 and n-3 EFAs have raised interest as novel anti-cancer
agents as they have been shown to exert a number of selective
cytotoxic and anti-proliferative effects on human cancer cells
without affecting normal tissues.2 In vitro experiments have identified
a variety of EFA anti-tumour actions. These include direct
cytotoxicity via liberation of free radicals and lipid peroxides;
up-regulation of cell surface adhesion molecules; inhibition of
angiogenesis; induction of apoptosis; interaction with secondary
messenger and cell-signalling pathways and modulation of cellular
receptor structure and function including steroid hormone receptors.
3 A number of animal studies have demonstrated inhibitory
effects of dietary supplementation of EFAs on experimental tumours.
4–6 More recently, pilot clinical trials of GLA have
achieved useful tumour regression and improved quality of life
with negligible systemic toxicity in a variety of advanced solid
malignancies.7–10

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