Dietary exposure to whey proteins alters rat mammary gland proliferation, apoptosis, and gene expression during postnatal development.
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 (beta-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 beta-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.
Eason
Renea R
RR
Arkansas Children's Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA.
Velarde
Michael C
MC
Chatman
Leon
L
Till
S Reneé
SR
Geng
Yan
Y
Ferguson
Matthew
M
Badger
Thomas M
TM
Simmen
Rosalia C M
RC
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D004044:Dietary Proteins / Q000494:pharmacology*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D008321:Mammary Glands, Animal / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008894:Milk Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D051059:PTEN Phosphohydrolase; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067816:Whey Proteins
D004044:Dietary Proteins; D008894:Milk Proteins; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D000067816:Whey Proteins; D015127:9,10-Dimethyl-1,2-benzanthracene; D017027:Protein Tyrosine Phosphatases; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat