Experimental hypothyroidism increases apoptosis in dimethylbenzanthracene-induced mammary tumors

López-Fontana,Constanza  Matilde; Sasso,Corina   Verónica; Maselli,María  Eugenia; Santiano,Flavia  Eliana; Semino,Silvana  Noemí; Cuello Carrión
,Fernando   Darío; Jahn,Graciela  Alma; Carón,Rubén  Walter

doi:10.3892/or.2013.2648

Experimental hypothyroidism increases apoptosis in dimethylbenzanthracene-induced mammary tumors

Authors:
- Constanza Matilde López-Fontana
- Corina Verónica Sasso
- María Eugenia Maselli
- Flavia Eliana Santiano
- Silvana Noemí Semino
- Fernando Darío Cuello Carrión
- Graciela Alma Jahn
- Rubén Walter Carón
View Affiliations

Affiliations: Institute of Medicine and Experimental Biology of Cuyo, CONICET, CCT-Mendoza, Mendoza, Argentina, Department of Diagnosis and Treatment, Laboratory of Pathological Anatomy, University Hospital, National University of Cuyo, Mendoza, Argentina
Published online on: August 1, 2013 https://doi.org/10.3892/or.2013.2648
Pages: 1651-1660

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

Epidemiological and in vitro data have not provided conclusive evidence concerning the involvement of thyroid hormones (THs) on mammary carcinogenesis. We used an in vivo model to assess the relationship between THs, adipose tissue and breast cancer development. Female Sprague‑Dawley rats were treated with a dose of 7,12-dimethylbenz(a)anthracene (15 mg/rat) at 55 days of age and were then divided into four experimental groups: hypothyroid rats (HypoT, 0.01% 6-N-propyl-2-thiouracil in drinking water), untreated control (EUT); hyperthyroid rats (HyperT, 0.25 mg/kg/day T4 s.c.) and vehicle-treated control rats. The latency of tumor appearance and the incidence and progression of tumors were determined. At sacrifice, blood samples were collected for hormone determinations and samples of tumor and mammary glands were obtained for immunohistological studies. HypoT rats had retarded growth and an increase in mammary fat. The latency was longer (p<0.0001), the incidence rate was lower (p<0.05) and tumor growth was slower in HypoT rats compared to EUT and HyperT rats. Mitotic index and PCNA immunostaining were similar in all groups. HypoT rats showed increased apoptosis (p<0.05) as evaluated by the apoptotic index and TUNEL staining. No differences in serum prolactin and progesterone were observed. However, circulating estradiol (E2) was significantly lower in HypoT and HyperT rats. Serum leptin levels were reduced in HypoT rats even though the abdominal fat mass was similar in all groups. To note, the leptin level was higher in HypoT rats that developed mammary tumors than the level in non-tumoral HypoT rats. In conclusion, hypothyroidism altered animal growth, breast morphology, body composition, leptin secretion and serum E2 enhancing apoptosis and, consequently, retarding mammary carcinogenesis in rats.

View Figures

View References

1	Neville MC, McFadden TB and Forsyth I: Hormonal regulation of mammary differentiation and milk secretion. J Mammary Gland Biol Neoplasia. 7:49–66. 2002. View Article : Google Scholar : PubMed/NCBI
2	Jensen EV, Cheng G, Palmieri C, Saji S, Mäkelä S, Van Noorden S, Wahlström T, Warner M, Coombes RC and Gustafsson JA: Estrogen receptors and proliferation markers in primary and recurrent breast cancer. Proc Natl Acad Sci USA. 98:15197–15202. 2001. View Article : Google Scholar : PubMed/NCBI
3	Lanari C and Molinolo AA: Progesterone receptors - animal models and cell signalling in breast cancer. Diverse activation pathways for the progesterone receptor: possible implications for breast biology and cancer. Breast Cancer Res. 4:240–243. 2002. View Article : Google Scholar
4	Clevenger CV, Furth PA, Hankinson SE and Schuler LA: The role of prolactin in mammary carcinoma. Endocr Rev. 24:1–27. 2003. View Article : Google Scholar : PubMed/NCBI
5	Frontini L, Lissoni P, Vaghi M, Perego MS, Pescia S, Ardizzoia A and Gardani G: Enhancement of the efficacy of weekly low-dose taxotere by the long acting anti-prolactinemic drug cabergoline in pretreated metastatic breast cancer. Anticancer Res. 24:4223–4226. 2004.PubMed/NCBI
6	Shen Q, Lantvit DD, Lin Q, Li Y, Christov K, Wang Z, Unterman TG, Mehta RG and Swanson SM: Advanced rat mammary cancers are growth hormone dependent. Endocrinology. 148:4536–4544. 2007. View Article : Google Scholar : PubMed/NCBI
7	Angelousi AG, Anagnostou VK, Stamatakos MK, Georgiopoulos GA and Kontzoglou KC: Mechanisms in endocrinology: primary HT and risk for breast cancer: a systematic review and meta-analysis. Eur J Endocrinol. 166:373–381. 2012. View Article : Google Scholar : PubMed/NCBI
8	Cristofanilli M, Yamamura Y, Kau SW, Bevers T, Strom S, Patangan M, Hsu L, Krishnamurthy S, Theriault RL and Hortobagyi GN: Thyroid hormone and breast carcinoma. Primary hypothyroidism is associated with a reduced incidence of primary breast carcinoma. Cancer. 103:1122–1128. 2005.PubMed/NCBI
9	Barrera-Hernandez G, Park KS, Dace A, Zhan Q and Cheng SY: Thyroid hormone-induced cell proliferation in GC cells is mediated by changes in G1 cyclin/cyclin-dependent kinase levels and activity. Endocrinology. 140:5267–5274. 1999. View Article : Google Scholar : PubMed/NCBI
10	Jeong YJ, Bong JG, Park SH, Choi JH and Oh HK: Expression of leptin, leptin receptor, adiponectin, and adiponectin receptor in ductal carcinoma in situ and invasive breast cancer. J Breast Cancer. 14:96–103. 2011. View Article : Google Scholar : PubMed/NCBI
11	Goodman AD, Hoekstra SJ and Marsh PS: Effects of hypothyroidism on the induction and growth of mammary cancer induced by 7,12-dimethylbenz(a)anthracene in the rat. Cancer Res. 40:2336–2342. 1980.PubMed/NCBI
12	Giovambattista A, Piermaria J, Suescun MO, Calandra RS, Gaillard RC and Spinedi E: Direct effect of ghrelin on leptin production by cultured rat white adipocytes. Obesity. 14:19–27. 2006. View Article : Google Scholar : PubMed/NCBI
13	Russo J and Russo IH: Atlas and histologic classification of tumors of the rat mammary gland. J Mammary Gland Biol Neoplasia. 5:187–200. 2000. View Article : Google Scholar : PubMed/NCBI
14	López-Fontana CM, Maselli ME, Salicioni AM and Carón RW: The inhibitory effect of progesterone on lactogenesis during pregnancy is already evident by mid- to late gestation in rodents. Reprod Fertil Dev. 24:704–714. 2012.PubMed/NCBI
15	Cuello-Carrión FD and Ciocca DR: Improved detection of apoptotic cells using a modified in situ TUNEL technique. J Histochem Cytochem. 47:837–839. 1999.PubMed/NCBI
16	Vazquez-Prieto MA, Renna NF, Diez ER, Cacciamani V, Lembo C and Miatello RM: Effect of red wine on adipocytokine expression and vascular alterations in fructose-fed rats. Am J Hypertens. 24:234–240. 2011. View Article : Google Scholar : PubMed/NCBI
17	Ito K and Maruchi N: Breast cancer in patients with Hashimoto’s thyroiditis. Lancet. 2:1119–1121. 1975.
18	Shering SG, Zbar AP, Moriarty M, McDermott EW, O’Higgins NJ and Smyth PP: Thyroid disorders and breast cancer. Eur J Cancer Prev. 5:504–506. 1996.
19	Nogueira CR and Brentani MM: Triiodothyronine mimics the effects of estrogen in breast cancer cell lines. J Steroid Biochem Mol Biol. 59:271–279. 1996. View Article : Google Scholar : PubMed/NCBI
20	Brinton LA, Hoffman DA, Hoover R and Fraumeni JF Jr: Relationship of thyroid disease and use of thyroid supplements to breast cancer risk. J Chronic Dis. 37:877–893. 1984. View Article : Google Scholar : PubMed/NCBI
21	Martinez-Iglesias O, Garcia-Silva S, Regadera J and Aranda A: Hypothyroidism enhances tumor invasiveness and metastasis development. PLoS One. 4:e64282009. View Article : Google Scholar : PubMed/NCBI
22	Hardefeldt PJ, Eslick GD and Edirimanne S: Benign thyroid disease is associated with breast cancer: a meta-analysis. Breast Cancer Res Treat. 133:1169–1177. 2012. View Article : Google Scholar : PubMed/NCBI
23	Kapdi CC and Wolfe JN: Breast cancer. Relationship to thyroid supplements for hypothyroidism. JAMA. 236:1124–1127. 1976. View Article : Google Scholar : PubMed/NCBI
24	Mustacchi P and Greenspan F: Thyroid supplementation for hypothyroidism. An latrogenic cause of breast cancer? JAMA. 237:1446–1447. 1977. View Article : Google Scholar : PubMed/NCBI
25	Saraiva PP, Figueiredo NB, Padovani CR, Brentani MM and Nogueira CR: Profile of thyroid hormones in breast cancer patients. Braz J Med Biol Res. 38:761–765. 2005. View Article : Google Scholar : PubMed/NCBI
26	Raccurt M, Lobie PE, Moudilou E, Garcia-Caballero T, Frappart L, Morel G and Mertani HC: High stromal and epithelial human gh gene expression is associated with proliferative disorders of the mammary gland. J Endocrinol. 175:307–318. 2002. View Article : Google Scholar : PubMed/NCBI
27	Kleinberg DL, Wood TL, Furth PA and Lee AV: Growth hormone and insulin-like growth factor-I in the transition from normal mammary development to preneoplastic mammary lesions. Endocr Rev. 30:51–74. 2009. View Article : Google Scholar : PubMed/NCBI
28	Thijssen JH: On the possible role of mammary-derived growth hormone in human breast cancer. Maturitas. 65(Suppl 1): S13–S16. 2009. View Article : Google Scholar : PubMed/NCBI
29	Hapon MB, Gamarra-Luques C and Jahn GA: Short term hypothyroidism affects ovarian function in the cycling rat. Reprod Biol Endocrinol. 8:142010. View Article : Google Scholar : PubMed/NCBI
30	Rinaldi S, Toniolo P, Muti P, Lundin E, Zeleniuch-Jacquotte A, Arslan A, Micheli A, Lenner P, Dossus L, Krogh V, Shore RE, Koenig KL, Riboli E, Stattin P, Berrino F, Hallmans G, Lukanova A and Kaaks R: IGF-I, IGFBP-3 and breast cancer in young women: a pooled re-analysis of three prospective studies. Eur J Cancer Prev. 14:493–496. 2005. View Article : Google Scholar : PubMed/NCBI
31	Kaulsay KK, Mertani HC, Törnell J, Morel G, Lee KO and Lobie PE: Autocrine stimulation of human mammary carcinoma cell proliferation by human growth hormone. Exp Cell Res. 250:35–50. 1999. View Article : Google Scholar : PubMed/NCBI
32	Mukhina S, Mertani HC, Guo K, Lee KO, Gluckman PD and Lobie PE: Phenotypic conversion of human mammary carcinoma cells by autocrine human growth hormone. Proc Natl Acad Sci USA. 101:15166–15171. 2004. View Article : Google Scholar : PubMed/NCBI
33	Russo J, Lynch H and Russo IH: Mammary gland architecture as a determining factor in the susceptibility of the human breast to cancer. Breast J. 7:278–291. 2001. View Article : Google Scholar : PubMed/NCBI
34	Tan J, Buache E, Chenard MP, Dali-Youcef N and Rio MC: Adipocyte is a non-trivial, dynamic partner of breast cancer cells. Int J Dev Biol. 55:851–859. 2011. View Article : Google Scholar : PubMed/NCBI
35	Neville MC, Medina D, Monks J and Hovey RC: The mammary fat pad. J Mammary Gland Biol Neoplasia. 3:109–116. 1998. View Article : Google Scholar
36	Petersen OW, Rønnov-Jessen L, Weaver VM and Bissell MJ: Differentiation and cancer in the mammary gland: shedding light on an old dichotomy. Adv Cancer Res. 75:135–161. 1998. View Article : Google Scholar : PubMed/NCBI
37	Vonderhaar BK and Greco AE: Effect of thyroid status on development of spontaneous mammary tumors in primiparous C3H mice. Cancer Res. 42:4553–4561. 1982.PubMed/NCBI
38	Vonderhaar BK and Greco AE: Lobulo-alveolar development of mouse mammary glands is regulated by thyroid hormones. Endocrinology. 104:409–418. 1979. View Article : Google Scholar : PubMed/NCBI
39	Knight BB, Oprea-Ilies GM, Nagalingam A, Yang L, Cohen C, Saxena NK and Sharma D: Survivin upregulation, dependent on leptin-EGFR-Notch1 axis, is essential for leptin-induced migration of breast carcinoma cells. Endocr Relat Cancer. 18:413–428. 2011. View Article : Google Scholar : PubMed/NCBI
40	Zhou W, Guo S and Gonzalez-Perez RR: Leptin pro-angiogenic signature in breast cancer is linked to IL-1 signalling. Br J Cancer. 104:128–137. 2011. View Article : Google Scholar : PubMed/NCBI
41	Mantzoros CS: The role of leptin in human obesity and disease: a review of current evidence. Ann Intern Med. 130:671–680. 1999. View Article : Google Scholar : PubMed/NCBI
42	Valcavi R, Zini M, Peino R, Casanueva FF and Dieguez C: Influence of thyroid status on serum immunoreactive leptin levels. J Clin Endocrinol Metab. 82:1632–1634. 1997.PubMed/NCBI
43	Sreenan S, Caro JF and Refetoff S: Thyroid dysfunction is not associated with alterations in serum leptin levels. Thyroid. 7:407–409. 1997. View Article : Google Scholar : PubMed/NCBI
44	Leonhardt U, Ritzel U, Schäfer G, Becker W and Ramadori G: Serum leptin levels in hypo- and hyperthyroidism. J Endocrinol. 157:75–79. 1998. View Article : Google Scholar : PubMed/NCBI
45	Housa D, Housová J, Vernerová Z and Haluzik M: Adipocytokines and cancer. Physiol Res. 55:233–244. 2006.
46	Rose DP, Gilhooly EM and Nixon DW: Adverse effects of obesity on breast cancer prognosis, and the biological actions of leptin (Review). Int J Oncol. 21:1285–1292. 2002.PubMed/NCBI
47	Artwohl M, Roden M, Hölzenbein T, Freudenthaler A, Waldhäusl W and Baumgartner-Parzer SM: Modulation by leptin of proliferation and apoptosis in vascular endothelial cells. Int J Obes Relat Metab Disord. 26:577–580. 2002. View Article : Google Scholar : PubMed/NCBI
48	Pasqualini JR: Breast cancer and steroid metabolizing enzymes: the role of progestogens. Maturitas. 65(Suppl 1): S17–S21. 2009. View Article : Google Scholar : PubMed/NCBI
49	Bolton JL and Thatcher GR: Potential mechanisms of estrogen quinone carcinogenesis. Chem Res Toxicol. 21:93–101. 2008. View Article : Google Scholar : PubMed/NCBI
50	Goepfert TM, McCarthy M, Kittrell FS, Stephens C, Ullrich RL, Brinkley BR and Medina D: Progesterone facilitates chromosome instability (aneuploidy) in p53 null normal mammary epithelial cells. FASEB J. 14:2221–2229. 2000. View Article : Google Scholar : PubMed/NCBI