High susceptibility of heterozygous (+/fa) lean Zucker rats to 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis

Imai,Toshio; Cho,Young-Man; Takahashi,Mami; Kitahashi,Tsukasa; Takami,Shigeaki; Nishikawa,Akiyoshi; Ogawa,Kumiko

doi:10.3892/or.2013.2326

High susceptibility of heterozygous (+/fa) lean Zucker rats to 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis

Authors:
- Toshio Imai
- Young-Man Cho
- Mami Takahashi
- Tsukasa Kitahashi
- Shigeaki Takami
- Akiyoshi Nishikawa
- Kumiko Ogawa
View Affiliations

Affiliations: Central Animal Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan, Division of Pathology, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan
Published online on: March 5, 2013 https://doi.org/10.3892/or.2013.2326
Pages: 1914-1922

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Susceptibility to 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis was investigated in lean Zucker (+/fa) rats carrying one mutated leptin receptor gene and wild-type controls (+/+). Rats with both genotypes were given a single DMBA administration and divided into two groups, one group was fed on basal diet mixed with 10% corn oil and the other was fed on basal diet alone. The minimum latency period of palpable carcinomas in +/fa rats of both groups was 8 weeks following DMBA treatment, in contrast to the 11-12 weeks in +/+. The incidence and multiplicity of carcinomas increased or showed a tendency for increase in the early stages in +/fa rats of both groups as compared to the +/+ counterparts. The volumes of carcinomas showed a tendency to increase in the corn oil diet groups of both genotypes. The major histopathological phenotype of carcinomas in all groups was well-differentiated without distinct atypia (multiplicity, 0.69-1.09/rat), but moderately/poorly differentiated carcinomas with atypia were also found, predominantly in +/fa rats (0.09-0.21). These latter tumors were characterized by elevated ERK activity but not estrogen receptor expression. Serum leptin concentrations in +/fa rats at 7 weeks of age were higher than those in +/+ and were elevated by the corn oil diet; however, no obvious change was detected in other serum parameters examined. In conclusion, +/fa rats proved more susceptible to DMBA-induced mammary carcinogenesis than +/+ controls, and hyperleptinemia was suggested to contribute to tumor growth as well as to susceptibility to tumorigenesis and more aggressive phenotypes in Zucker lean rats.

View Figures

View References

1	van den Brandt PA, Spiegelman D, Yaun SS, et al: Pooled analysis of prospective cohort studies on height, weight, and breast cancer risk. Am J Epidemiol. 152:514–527. 2000.PubMed/NCBI
2	Lahmann PH, Hoffmann K, Allen N, et al: Body size and breast cancer risk: findings from the European Prospective Investigation into Cancer and Nutrition (EPIC). Int J Cancer. 111:762–771. 2004. View Article : Google Scholar : PubMed/NCBI
3	Reeves GK, Pirie K, Beral V, Green J, Spencer E and Bull D: Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study. BMJ. 335:11342007. View Article : Google Scholar : PubMed/NCBI
4	Iwasaki M, Otani T, Inoue M, Sasazuki S and Tsugane S: Body size and risk for breast cancer in relation to estrogen and progesterone receptor status in Japan. Ann Epidemiol. 17:304–312. 2007. View Article : Google Scholar : PubMed/NCBI
5	Key TJ, Appleby PN, Reeves GK, et al: Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst. 95:1218–1226. 2003. View Article : Google Scholar : PubMed/NCBI
6	Auwerx J and Staels B: Leptin. Lancet. 351:737–742. 1998. View Article : Google Scholar
7	Wu MH, Chou YC, Chou WY, et al: Circulating levels of leptin, adiposity and breast cancer risk. Br J Cancer. 100:578–582. 2009. View Article : Google Scholar : PubMed/NCBI
8	Soma D, Kitayama J, Yamashita H, Miyato H, Ishikawa M and Nagawa H: Leptin augments proliferation of breast cancer cells via transactivation of HER2. J Surg Res. 149:9–14. 2008. View Article : Google Scholar : PubMed/NCBI
9	Saxena NK, Taliaferro-Smith L, Knight BB, et al: Bidirectional crosstalk between leptin and insulin-like growth factor-I signaling promotes invasion and migration of breast cancer cells via transactivation of epidermal growth factor receptor. Cancer Res. 68:9712–9722. 2008. View Article : Google Scholar
10	Cirillo D, Rachiglio AM, la Montagna R, Giordano A and Normanno N: Leptin signaling in breast cancer: an overview. J Cell Biochem. 105:956–964. 2008. View Article : Google Scholar : PubMed/NCBI
11	Chua SC Jr, Chung WK, Wu-Peng XS, et al: Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science. 271:994–996. 1996. View Article : Google Scholar : PubMed/NCBI
12	Bray GA: The Zucker-fatty rat: a review. Fed Proc. 36:148–153. 1977.
13	Rayner DV, Dalgliesh GD, Duncan JS, Hardie LJ, Hoggard N and Trayhurn P: Postnatal development of the ob gene system: elevated leptin levels in suckling fa/fa rats. Am J Physiol. 273:R446–R450. 1997.PubMed/NCBI
14	Lee WM, Lu S, Medline A and Archer MC: Susceptibility of lean and obese Zucker rats to tumorigenesis induced by N-methyl-N-nitrosourea. Cancer Lett. 162:155–160. 2001. View Article : Google Scholar : PubMed/NCBI
15	Hakkak R, Holley AW, Macleod SL, et al: Obesity promotes 7,12-dimethylbenz(a)anthracene-induced mammary tumor development in female zucker rats. Breast Cancer Res. 7:R627–R633. 2005. View Article : Google Scholar : PubMed/NCBI
16	Hakkak R, MacLeod S, Shaaf S, et al: Obesity increases the incidence of 7,12-dimethylbenz(a)anthracene-induced mammary tumors in an ovariectomized Zucker rat model. Int J Oncol. 30:557–563. 2007.PubMed/NCBI
17	de Assis S, Wang M, Goel S, Foxworth A, Helferich W and Hilakivi-Clarke L: Excessive weight gain during pregnancy increases carcinogen-induced mammary tumorigenesis in Sprague-Dawley and lean and obese Zucker rats. J Nutr. 136:998–1004. 2006.PubMed/NCBI
18	Cho YM, Imai T, Takami S, Ogawa K and Nishikawa A: Female heterozygous (+/fa) Zucker rats as a novel leptin-related mammary carcinogenesis model. J Toxicol Sci. 37:1025–1034. 2012.
19	Phillips MS, Liu Q, Hammond HA, et al: Leptin receptor missense mutation in the fatty Zucker rat. Nat Genet. 13:18–19. 1996. View Article : Google Scholar : PubMed/NCBI
20	Imai T, Cho YM, Hasumura M and Hirose M: Enhancement by acrylamide of N-methyl-N-nitrosourea-induced rat mammary tumor development-possible application for a model to detect co-modifiers of carcinogenesis. Cancer Lett. 230:25–32. 2005.PubMed/NCBI
21	Cho YM, Imai T, Hasumura M and Hirose M: Lack of enhancement of susceptibility to mammary and thyroid carcinogenesis in rats exposed to DMBA and DHPN following prepubertal iodine deficiency. Cancer Sci. 97:1031–1036. 2006. View Article : Google Scholar : PubMed/NCBI
22	Ip C, Carter CA and Ip MM: Requirement of essential fatty acid for mammary tumorigenesis in the rat. Cancer Res. 45:1997–2001. 1985.PubMed/NCBI
23	Mauro L, Catalano S, Bossi G, et al: Evidences that leptin up-regulates E-cadherin expression in breast cancer: effects on tumor growth and progression. Cancer Res. 67:3412–3421. 2007. View Article : Google Scholar : PubMed/NCBI
24	Thordarson G, Lee AV, McCarty M, et al: Growth and characterization of N-methyl-N-nitrosourea-induced mammary tumors in intact and ovariectomized rats. Carcinogenesis. 22:2039–2047. 2001.PubMed/NCBI
25	Coutts AS and Murphy LC: Elevated mitogen-activated protein kinase activity in estrogen-non responsive human breast cancer cells. Cancer Res. 58:4071–4074. 1998.PubMed/NCBI
26	Gomez SL, Quach T, Horn-Ross PL, et al: Hidden breast cancer disparities in Asian women: disaggregating incidence rates by ethnicity and migrant status. Am J Public Health. 100(Suppl 1): S125–S131. 2010. View Article : Google Scholar : PubMed/NCBI
27	Kalhan R, Puthawala K, Agarwal S, Amini SB and Kalhan SC: Altered lipid profile, leptin, insulin, and anthropometry in offspring of South Asian immigrants in the United States. Metabolism. 50:1197–1202. 2001. View Article : Google Scholar : PubMed/NCBI
28	Ghumare SS and Cunningham JE: Breast cancer trends in Indian residents and emigrants portend an emerging epidemic for India. Asian Pac J Cancer Prev. 8:507–512. 2007.PubMed/NCBI
29	Lim SE, Back M, Quek E, Iau P, Putti T and Wong JE: Clinical observations from a breast cancer registry in Asian women. World J Surg. 31:1387–1392. 2007. View Article : Google Scholar : PubMed/NCBI
30	Ishikawa M, Kitayama J and Nagawa H: Enhanced expression of leptin and leptin receptor (OB-R) in human breast cancer. Clin Cancer Res. 10:4325–4331. 2004. View Article : Google Scholar : PubMed/NCBI
31	Garofalo C, Koda M, Cascio S, et al: Increased expression of leptin and the leptin receptor as a marker of breast cancer progression: possible role of obesity-related stimuli. Clin Cancer Res. 12:1447–1453. 2006. View Article : Google Scholar : PubMed/NCBI
32	Ray A, Nkhata KJ and Cleary MP: Effects of leptin on human breast cancer cell lines in relationship to estrogen receptor and HER2 status. Int J Oncol. 30:1499–1509. 2007.PubMed/NCBI
33	Iwasaki M, Otani T, Inoue M, Sasazuki S and Tsugane S: Role and impact of menstrual and reproductive factors on breast cancer risk in Japan. Eur J Cancer Prev. 16:116–123. 2007. View Article : Google Scholar : PubMed/NCBI
34	Grossmann ME, Ray A, Nkhata KJ, et al: Obesity and breast cancer: status of leptin and adiponectin in pathological processes. Cancer Metastasis Rev. 29:641–653. 2010. View Article : Google Scholar : PubMed/NCBI
35	Hjartaker A, Langseth H and Weiderpass E: Obesity and diabetes epidemics: cancer repercussions. Adv Exp Med Biol. 630:72–93. 2008. View Article : Google Scholar : PubMed/NCBI