Elsevier

The Journal of Nutrition

Volume 134, Issue 12, December 2004, Pages 3370-3377
The Journal of Nutrition

Dietary Exposure to Whey Proteins Alters Rat Mammary Gland Proliferation, Apoptosis, and Gene Expression during Postnatal Development1

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We have found that AIN-93G diets made with whey protein hydrolysate (WPH) reduce 7,12-dimethyl-benz[a]anthracene (DMBA)-induced tumor incidence in Sprague-Dawley (Harlan) rats relative to those fed a diet with casein (CAS). Herein, we replicated these findings in another Sprague-Dawley substrain (Charles River) and examined whether WPH protective effects were associated with altered mammary gland differentiation status and expression of the tumor suppressor phosphatase and tensin homolog deleted in chromosome ten (PTEN). Mammary tumor incidence was lower in DMBA-treated rats fed WPH than in those fed CAS. Mammary glands of WPH- and CAS-fed rats were isolated at weaning [postnatal day (PND) 21–28] and at an early adult stage (PND 50–53) and analyzed for proliferative (proliferating cell nuclear antigen immunoreactivity), apoptotic (terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick-end labeling), and differentiation (β-casein) indices, as well as for PTEN mRNA and protein levels. PND 50–53 rats fed WPH showed decreased proliferation and increased apoptosis in mammary structures, coincident with increased mammary β-casein gene expression, decreased terminal end-bud numbers, and increased ductal lengths, relative to same-age CAS-fed rats. When challenged with DMBA for 24 h, mammary glands of PND 53 CAS-fed rats had decreased cell survival in both terminal end buds and ductal epithelium, while the mammary glands of WPH-fed rats were not altered from pre-DMBA levels. At 7 d post-DMBA, mammary glands of CAS- and WPH-fed rats exhibited comparable apoptotic indices. Mammary PTEN expression was higher in WPH- than in CAS-fed rats at PND 21–28, but was not different in young adults fed either diet. Results demonstrate that dietary WPH advances mammary gland differentiation during neonatal development and suggest that the transiently increased expression of the pro-apoptotic signal PTEN during a sensitive developmental window may partly underlie the cancer protective effects of WPH.

Key words:

mammary gland
development
cancer
PTEN
whey proteins

Abbreviations used:

CAS
casein
DE
ductal epithelium
DMBA
7,12-dimethyl-benz[a]anthracene
IGF
insulin-like growth factor
MAPK
mitogen activated protein kinase
PCNA
proliferating cell nuclear antigen
PND
postnatal day
PR
progesterone receptor
PTEN
phosphatase and tensin homolog deleted in chromosome ten
QPCR
quantitative real-time polymerase chain reaction
SPI
soy protein isolate
TEB
terminal end buds
TUNEL
terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick-end labeling
WPH
whey protein hydrolysate

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1

Funds for this research were provided by the USDA-CRIS-6251–5100002–06S to the Arkansas Children's Nutrition Center.