Carcinogenesis Advance Access originally published online on September 4, 2006
Carcinogenesis 2007 28(3):545-552; doi:10.1093/carcin/bgl166
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Compensatory mammary growth following protein restriction during pregnancy and lactation increases early-onset mammary tumor incidence in rats
Department of Clinical Biochemistry, University of Cambridge Addenbrookes Hospital, Cambridge CB2 2QR, UK
1 Division of Cancer Sciences and Molecular Pathology, Section of Gene Regulation and Mechanisms of Disease Department of Pathology, University of Glasgow, Western Infirmary, Glasgow G11 6NT, UK
2 MRC Epidemiology Unit, Strangeways Research Laboratory Worts Causeway, Cambridge, CB1 8RN, UK
*To whom correspondence should be addressed at: Department of Clinical Biochemistry, University of Cambridge, Box 232 Level 4, Addenbrookes Hospital, Hills Road, Cambridge, CB2 2QR, UK. Tel: +44 1223 336784; Fax: +44 1223 330598; Email: df220{at}cam.ac.uk
Breast cancer incidence is increased in women with both high and low birth weight. The latter is also associated with hyperglycaemia, insulin resistance and type-2 diabetes, each of which independently increases breast cancer risk. We showed previously in our model of poor early-growth that pregnancy estradiol levels were raised while offspring developed type-2 diabetes. We hypothesized that nutritionally-induced poor early-growth influences breast cancer risk and investigated this in our model. Wistar rat dams were given either a control diet (20% casein) or an isocaloric low-protein (LP) diet (8% casein) throughout pregnancy and lactation. Offspring postnatal mammary gland development was assessed by morphometry. To identify potential growth mechanisms, we measured protein expression of receptors involved in insulin and hormone signaling, both in cleared mammary gland lysates and isolated epithelial cells. Mammary tumor incidence and latency (n = 96) was monitored after three weekly intraperitoneal nitrosomethylurea injections (50 mg/kg body wt). LP offspring displayed reduced postnatal ductal branching and epithelial invasion at 3 weeks, followed by compensatory mammary growth 1 week later coinciding with increased protein expression of receptors to insulin, IGF-1 and estrogen. Significantly, early-mammary tumor incidence (0–16 weeks post-treatment) was doubled in LP offspring [RR, 2.13 (1.02, 4.45); P = 0.046]. The data suggest that poor early nutrition has an important influence on the mammary primordium, and increases future susceptibility to breast cancer. Up-regulated growth factor and hormone signaling during compensatory mammary growth may mediate this increased susceptibility and present potential targets for intervention.
Abbreviations: ER
/ERß, estrogen receptor isoform alpha/beta; IGF-1, insulin-like growth factor-1; IGF-1Rß, insulin-like growth factor-1 receptor beta subunit; IR, insulin receptor; LP, low-protein; NMU, nitrosomethylurea
Received May 15, 2006; revised August 24, 2006; accepted August 25, 2006.