Carcinogenesis, Vol 18, 2271-2276, Copyright © 1997 by Oxford University Press
AR Tagliaferro, AM Ronan, LD Meeker, HJ Thompson and AL Scott
We reported recently that weight cycling significantly increased the
incidence of mammary cancer in virgin female rats that were pretreated with
N-methyl-N-nitrosourea. The present study investigated the effect of weight
cycling on mammary epithelial cell proliferation and its relationship to
changes in plasma insulin, estrogen, progesterone and urinary
corticosterone in 30 female virgin Sprague-Dawley rats. Animals were fed a
modified AIN-76A diet containing 24.6% corn oil by weight. Weight-cycled
(WC) rats were food restricted daily by either 33% or 50% of non-restricted
controls for 1 week followed by 3 weeks compensatory refeeding and weight
recovery over 18 weeks or 4.5 weight cycles. WC rats consumed 6-10% less
food than controls (P = 0.01) but showed a 71- 89% greater efficiency of
food utilization for growth (P < 0.0001) than controls. There were no
differences in total weight gain during treatment. Mammary lobuloalveolar
and ductal cell proliferation of WC rats, measured by
5-bromo-2'deoxyuridine labelling, increased in a dose- response fashion, P
= 0.03, P = 0.06 respectively in comparison to controls. Energy and
substrate utilization measured by indirect calorimetry indicated WC animals
expended less energy (P = 0.005) and utilized less glucose (P = 0.0001) and
protein (P = 0.006) during restriction, and less lipid during recovery (P =
0.05) than controls. There were no significant differences in hormone
levels between groups. Multiple regression analysis with plasma insulin,
estrogen, progesterone and urinary corticosterone as independent variables
(r = 0.947, r2 = 0.897, P = 0.003) showed that plasma insulin was the only
significant predictor (P < 0.01) of mammary cell proliferation. In
accord with this observation, tyrosine-phosphorylated activation of insulin
receptor substrate-1, detected by immunoprecipitation and Western
immunoblot analysis in mammary tumors of WC rats from our previous study,
was 3-5 times greater than in non-restricted controls (P < 0.01).
Present findings suggest that weight cycling in rats increases risk of
breast cancer development via insulin stimulated mammary cell
proliferation.
ARTICLES
Cyclic food restriction, insulin and mammary cell proliferation in the rat
Department of Animal and Nutritional Sciences, University of New Hampshire, Durham 03824, USA.
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