Prepubertal physical activity up-regulates estrogen receptor β, BRCA1 and p53 mRNA expression in the rat mammary gland

被引:27
作者
Wang, M. [1 ]
Yu, B. [1 ]
Westerlind, K. [2 ]
Strange, R. [3 ]
Khan, G. [1 ]
Patil, D. [1 ]
Boeneman, K. [1 ]
Hilakivi-Clarke, L. [1 ]
机构
[1] Georgetown Univ, Dept Oncol, Washington, DC USA
[2] Univ Colorado, Hlth Sci Ctr, Div Endocrinol, Denver, CO USA
[3] Univ Colorado, Hlth Sci Ctr, Div Med Oncol, Denver, CO 80262 USA
关键词
Prepubertal physical activity; BRCA1; p53; Estrogen receptor; Terminal end bud; BREAST-CANCER RISK; PREMENOPAUSAL WOMEN; TUMOR-SUPPRESSOR; GENE-EXPRESSION; ER-ALPHA; METHYLATION; MUTATIONS; SUSCEPTIBILITY; PROLIFERATION; INHIBITION;
D O I
10.1007/s10549-008-0062-x
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Findings in BRCA1 mutation carriers suggest that physical activity, particularly during childhood, may be linked to a reduced risk of developing breast cancer. We investigated whether physical activity at puberty alters the expression of BRCA1 and two other tumor suppressor genes-p53 and estrogen receptor (ER)-beta-in rats. In addition, the effects on ER-alpha expression, mammary proliferation and functional epithelial differentiation were investigated as markers of altered mammary cancer risk in rats exposed to regular physical activity at puberty. Female Sprague Dawley rat pups were randomized to voluntary exercise, sham-exercise control and non-manipulated control groups. Treadmill training (20-25 m/min, 15% grade, 30 min/day, 5 days/week) started on postnatal day 14 and continued through day 32. Third thoracic mammary glands (n = 5 per group and age) were obtained at days 32, 48 and 100 and assessed for changes in morphology through wholemounts, and at 100 days cell proliferation by using Ki67 staining, protein levels of ER-alpha and ER-beta by immunohistochemistry, and mRNA expression levels of BRCA1, p53, ER-alpha and ER-beta by real-time PCR. Mammary glands of rats exposed to exercise during puberty contained fewer terminal end buds (TEBs) and a higher number of differentiated alveolar buds and lobules than the sham controls. However, cell proliferation was not significantly altered among the groups. ER-alpha protein levels were significantly reduced, while ER-beta levels were increased in the mammary ducts and lobular epithelial structures of 100-day old rays which were voluntarily exercised at puberty, compared to sham controls. ER-beta, BRCA1 and p53 mRNA levels were significantly higher in the mammary glands of 100-day-old exercised versus sham control rats. Pubertal physical activity reduced mammary epithelial targets for neoplastic transformation through epithelial differentiation and it also up-regulated tumor suppressor genes BRCA1, p53 and ER-beta, and reduced ER-alpha/ER-beta ratio in the mammary gland. It remains to be determined whether the up-regulation of BRCA1, and perhaps p53, explains the protective effect of childhood physical activity against breast cancer in women who carry a germline mutation in one of the BRCA1 alleles.
引用
收藏
页码:213 / 220
页数:8
相关论文
共 42 条
[1]   Models of genetic susceptibility to breast cancer [J].
Antoniou, A. C. ;
Easton, D. F. .
ONCOGENE, 2006, 25 (43) :5898-5905
[2]   Tumor suppressor p53 is required to modulate BRCA1 expression [J].
Arizti, P ;
Fang, L ;
Park, I ;
Yin, YX ;
Solomon, E ;
Ouchi, T ;
Aaronson, SA ;
Lee, SW .
MOLECULAR AND CELLULAR BIOLOGY, 2000, 20 (20) :7450-7459
[3]   Mammary Gland Development and Tumorigenesis in Estrogen Receptor Knockout Mice [J].
Bocchinfuso, Wayne P. ;
Korach, Kenneth S. .
JOURNAL OF MAMMARY GLAND BIOLOGY AND NEOPLASIA, 1997, 2 (04) :323-334
[4]   Are the TDLU of the human the same as the LA of mice? [J].
Cardiff, RD .
JOURNAL OF MAMMARY GLAND BIOLOGY AND NEOPLASIA, 1998, 3 (01) :3-5
[5]   Impact of estrogen receptor β on gene networks regulated by estrogen receptor α in breast cancer cells [J].
Chang, Edmund C. ;
Frasor, Jonna ;
Komm, Barry ;
Katzenellenbogen, Benita S. .
ENDOCRINOLOGY, 2006, 147 (10) :4831-4842
[6]   Estrogen receptors ERα and ERβ in proliferation in the rodent mammary gland [J].
Cheng, GJ ;
Zhang, WH ;
Warner, M ;
Gustafsson, JA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (11) :3739-3746
[7]  
Clarke RB, 1997, CANCER RES, V57, P4987
[8]  
Dobrovic A, 1997, CANCER RES, V57, P3347
[9]   BRCA1 inhibition of estrogen receptor signaling in transfected cells [J].
Fan, S ;
Wang, JA ;
Yuan, R ;
Ma, Y ;
Meng, Q ;
Erdos, MR ;
Pestell, RG ;
Yuan, F ;
Auborn, KJ ;
Goldberg, ID ;
Rosen, EM .
SCIENCE, 1999, 284 (5418) :1354-1356
[10]   Role of direct interaction in BRCA1 inhibition of estrogen receptor activity [J].
Fan, SJ ;
Ma, YX ;
Wang, CG ;
Yuan, RQ ;
Meng, QH ;
Wang, JA ;
Erdos, M ;
Goldberg, ID ;
Webb, P ;
Kushner, PJ ;
Pestell, RG ;
Rosen, EM .
ONCOGENE, 2001, 20 (01) :77-87