Profile of Histopathological Type and Molecular Subtypes of Mammary Cancer of DMBA-induced Rat and its Relevancy to Human Breast Cancer

Authors

  • Ika Fidianingsih Doctoral Program, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia; Department of Histology, Faculty of Medicine, Universitas Islam Indonesia, Yogyakarta, Indonesia https://orcid.org/0000-0002-1270-4545
  • Teguh Aryandono Department of Surgery, Oncology Division, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
  • Sitarina Widyarini Department of Pathology, Faculty of Veterinary Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
  • Sri Herwiyanti Department of Histology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia

DOI:

https://doi.org/10.3889/oamjms.2022.7975

Keywords:

7,12-Dimethylbenzanthracene, Estrogen receptor, Progesterone receptor, Human epidermal growth factor receptor 2, Ki67

Abstract

BACKGROUND: Animal models with mammary cancer that closely mimic human breast cancer for treatment development purposes are still required. Induction of 7,12-dimethylbenzanthracene (DMBA) to rats shows the histopathological features and mammary cancer characterization similar to humans. Examinations of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki67 expressions are crucial in deciding the treatment and prognosis of breast cancer.

AIM: This research aimed to view histopathology images of mammary glands and expressions of ER, PR, Ki67, and HER2 of DMBA-induced rats.

METHODS: After 1-week adaptation, 11 5-weeks-old female rats were induced with 20 mg/kg body weight (BW) of DMBA 2 times a week for 5 weeks. On week 29, nodules taken from the mammary gland were examined for hematoxylin-eosin staining and immunohistochemistry with p63, ER, PR, HER2, and Ki67 antibodies. The grading score used the Nottingham Grading System and molecular classifications based on St. Gallen 2013.

RESULTS: Six rats had nodules, but the histopathologic features of one nodule showed normal mammary gland without cancer. The histopathological type of mammary cancer was cribriform carcinoma, comedo carcinoma, lipid-rich carcinoma, adenocarcinoma squamous, and adenomyepithelioma. Histopathological grading showed 60% of grade 3 and 40% of grade 2. P63 expression showed 60% positive and 40% negative. The frequency of ER, PR, HER2, and Ki67 of five nodules showed positivity: 40%, 60%, 60%, and 60%, respectively. Molecular subtypes of Luminal A, B, HER2, and triple-negative were 0%, 60%, 20%, and 20%, respectively.

CONCLUSION: Histopathological features and molecular subtype of mammary cancer on rats induced with 20 mg/kg BW of DMBA showed similarity to human breast cancer.

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Plum Analytics Artifact Widget Block

References

World Health Organization. GLOBOCAN. 360 Indonesia Fact Sheet. Geneva: World Health Organization; 2020. Available from: https://gco.iarc.fr/today/data/factsheets/populations/360-indonesia-fact-sheets.pdf [Last accessed on 2021 May 10].

Carioli G, Bertuccio P, Boffetta P, Levi F, La Vecchia C, Negri E, et al. European cancer mortality predictions for the year 2020 with a focus on prostate cancer. Ann Oncol. 2020;31(5):650-8. https://doi.org/10.1016/j.annonc.2020.02.009 PMid:32321669 DOI: https://doi.org/10.1016/j.annonc.2020.02.009

Costa E, Ferreira-gonçalves T, Chasqueira G, Cabrita S. Experimental models as refined translational tools for breast cancer research. Sci Pharm. 2020;88(32):1-29. http://doi.org/10.3390/scipharm88030032 DOI: https://doi.org/10.3390/scipharm88030032

Liu Y, Yin T, Feng Y, Cona MM, Huang G, Liu J, et al. Mammalian models of chemically induced primary malignancies exploitable for imaging-based preclinical theragnostic research. Quant Imaging Med Surg. 2015;5(5):708-29. http://doi.org/10.3978/j.issn.2223-4292.2015.06.01 PMid:26682141

Dai X, Li T, Bai Z, Yang Y, Liu X, Zhan J, et al. Breast cancer intrinsic subtype classification, clinical use and future trends. Am J Cancer Res. 2015;5(10):2929-43. PMid:26693050 DOI: https://doi.org/10.1371/journal.pone.0124964

Nikolov S, Enchev E, Minkov G, Dimitrov E, Ivanova K, Gulubova M, et al. The role of the molecular subtypes in the prognosis of cancer patients. Open Access Maced J Med Sci. 2020;8(B):133-8. http://doi.org/10.3889/oamjms.2020.4077 DOI: https://doi.org/10.3889/oamjms.2020.4077

Cheung SY, Yuen MT, Choi HL, Cheng HK, Huang Y, Chen S, et al. An expression study of hormone receptors in spontaneously developed, carcinogen-induced and hormone-induced mammary tumors in female Noble rats. Int J Oncol. 2003;22(6):1383-95. PMid:12739009 DOI: https://doi.org/10.3892/ijo.22.6.1383

Russo J. Significance of rodent mammary tumors for human risk assessment. Toxicol Pathol. 2015;43(2):145. https://doi.org/10.1177/0192623314532036 PMid:25714400 DOI: https://doi.org/10.1177/0192623314532036

Charan J, Biswas T. How to calculate sample size for different study designs in medical research? Indian J Psychol Med. 2013;5(2):121-6. http://doi.org/10.4103/0253-7176.116232 PMid:24049221 DOI: https://doi.org/10.4103/0253-7176.116232

Goldschmidt MH, Peña L, Rasotto R, Zappulli V. Classification and grading of canine mammary tumors. Vet Pathol. 2011;48(1):117-131. http://doi.org/10.1177/0300985810393258 PMid:21266722 DOI: https://doi.org/10.1177/0300985810393258

Rudmann D, Cardiff R, Chouinard L, Goodman D, Küttler K, Marxfeld H, et al. Proliferative and nonproliferative lesions of the rat and mouse mammary, Zymbal’s, preputial, and clitoral glands. Toxicol Pathol. 2012;40 (6 Suppl):7-39. http://doi.org/10.1177/0192623312454242 PMid:22949413 DOI: https://doi.org/10.1177/0192623312454242

Nascimento RG do, Otoni KM. Histological and molecular classification of breast cancer: What do we know? Mastology. 2020;30:e20200024. http://doi.org/10.29289/25945394202020200024 DOI: https://doi.org/10.29289/25945394202020200024

Elston C, Ellis I. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: Experience from a large study with long-term follow-up. Histopathology. 1991;19(5):403-10. http://doi.org/10.1111/j.1365-2559.1991.tb00229.x PMid:25246403 DOI: https://doi.org/10.1111/j.1365-2559.1991.tb00229.x

Goldhirsch A, Winer EP, Coates AS, Gelber RD, Thürlimann B, Panel HS. Personalizing the treatment of women with early breast cancer: Highlights of the St gallen international expert consensus on the primary therapy of early breast cancer 2013. Ann Oncol. 2013;24(9):2206-23. http://doi.org/10.1093/annonc/mdt303 PMid:23917950 DOI: https://doi.org/10.1093/annonc/mdt303

Aiad H, Samaka R, Asaad N, Kandil M, Shehata M, Miligy I. Relationship of CK8/18 expression pattern to breast cancer immunohistochemical subtyping in Egyptian patients. ecancer Med Sci. 2014;8:404. http://doi.org/10.3332/ecancer.2014.404 PMid:24605136 DOI: https://doi.org/10.3332/ecancer.2014.404

Reisenbichler ES, Balmer NN, Adams AL, Pfeifer JD, Hameed O. Luminal cytokeratin expression profiles of breast papillomas and papillary carcinomas and the utility of a cytokeratin 5/p63/ cytokeratin 8/18 antibody cocktail in their distinction. Mod Pathol. 2011;24(2):185-93. http://doi.org/10.1038/modpathol.2010.197 PMid:21076459 DOI: https://doi.org/10.1038/modpathol.2010.197

Williams DL. Ocular disease in rats: A review. Vet Ophthalmol. 2002;5(3):183-91. http://doi.org/10.1046/j.1463-5224.2002.00251.x PMid:12236869 DOI: https://doi.org/10.1046/j.1463-5224.2002.00251.x

Smith JB, Mangkoewidjojo S. Pemeliharaan Pembiakan dan Penggunaan Hewan Percobaan di Daerah Tropis. Jakarta: Penerbit Universitas Indonesia; 1988.

Pritchett-Corning KR, Cosentino J, Clifford CB. Contemporary prevalence of infectious agents in laboratory mice and rats. Lab Anim. 2009;43(2):165-73. http://doi.org/10.1258/la.2008.008009 PMid:19015179 DOI: https://doi.org/10.1258/la.2008.008009

McInnes EF, Rasmussen L, Fung P, Auld AM, Alvarez L, Lawrence DA, et al. Prevalence of viral, bacterial and parasitological diseases in rats and mice used in research environments in Australasia over a 5-y period. Lab Anim (NY). 2011;40(11):341-50. http://doi.org/10.1038/laban1111-341 PMid:22012194 DOI: https://doi.org/10.1038/laban1111-341

Jangir BL, Chavhan S, Kurkure N, Chopade N. Diseases of laboratory rats. Livest Line. 2010;4(2):10-12.

Arora R, Bhushan S, Kumar R, Mannan R, Kaur P, Singh AP, et al. Hepatic dysfunction induced by 7, 12-dimethylbenz(α)anthracene and its obviation with erucin using enzymatic and histological changes as indicators. PLoS One. 2014;9(11):e112614. http://doi.org/10.1371/journal.pone.0112614 PMid:25390337 DOI: https://doi.org/10.1371/journal.pone.0112614

Al-Asady AM, Ghaleb NK, Alnasrawi AM, Alhamed TA. Effect of carcinogenic substance (7,12 dimethylbenz [a] anthracene (dmba)) on tissue, hematology character and enzyme activity in rat. Indian J Forensic Med Toxicol. 2020;14(1):1172-76. http://doi.org/10.37506/v14/i1/2020/ijfmt/193067

Gasparoto TH, De Oliveira CE, De Freitas LT, Pinheiro CR, Hori JI, Garlet GP, et al. Inflammasome activation is critical to the protective immune response during chemically induced squamous cell carcinoma. PLoS One. 2014;9(9):e107170. http://doi.org/10.1371/journal.pone.0107170 PMid:25268644 DOI: https://doi.org/10.1371/journal.pone.0107170

Miyata M, Furukawa M, Takahashi K, Gonzalez FJ, Yamazoe Y. Mechanism of 7,12-dimethylbenz[a]anthracene-induced immunotoxicity: role of metabolic activation at the target organ. Jpn J Pharmacol. 2001;86(3):302-9. http://doi.org/10.1254/jjp.86.302 PMid:11488430 DOI: https://doi.org/10.1254/jjp.86.302

Kocdor H, Cehreli R, Kocdor A, Sis B, Yilmaz O, Canda T, et al. Effects of selenium in Wistar rats. J Toxicol Environ Health. 2007;68(9):693-701. http://doi.org/10.1080/15287390590925438 DOI: https://doi.org/10.1080/15287390590925438

Alvarado A, Lopes AC, Faustino-Rocha AI, Cabrita MS, Ferreira R, Oliveira PA, et al. Animal and in vitro models prognostic factors in MNU and DMBA-induced mammary tumors in female rats. Pathol Pract. 2017;213:441-6. http://doi.org/10.1016/j.prp.2017.02.014 DOI: https://doi.org/10.1016/j.prp.2017.02.014

Russo J, Gusterson BA, Rogers AE, Russo IH, Wellings SR, Van Zwieten MJ. Comparative study of human and rat mammary tumorigenesis. Lab Investig. 1990;62(3):217-51. http://doi.org/10.1007/978-1-4612-0485-5_15 DOI: https://doi.org/10.1007/978-1-4612-0485-5_15

Wahyuniari IA, Arijana IG, Sriwidyani NP, Wiryanthini IA, Suwito H, Widyarini S, et al. The anticancer activity of (e)-1-(4’- aminophenyl)-3-phenylprop-2-en-1-on against DMBA-induced mammary cancer in Sprague Dawley rat through the regulation of microRNA-21 expression. Bali Med J. 2017;6(3):589. http://doi.org/10.15562/bmj.v6i3.697 DOI: https://doi.org/10.15562/bmj.v6i3.697

Guan B, Wang H, Cao S, Rao Q, Wang Y, Zhu Y, et al. Lipid-rich carcinoma of the breast clinicopathologic analysis of 17 cases. Ann Diagn Pathol. 2011;15(4):225-32. http://doi.org/10.1016/J.ANNDIAGPATH.2010.10.006 PMid:21396871 DOI: https://doi.org/10.1016/j.anndiagpath.2010.10.006

Rehm S. Chemical induced mammary gland adenomyoepitheliomas and myoepithelial carcinomas of mice: Immunohistochemical and ultrastructural features. Am J Pathol. 1990;136(3):575-84. PMid:1690510

Machida Y, Imai T. Different properties of mammary carcinogenesis induced by two chemical carcinogens, DMBA and PhIP, in heterozygous BALB/c Trp53 knockout mice. Oncol Lett. 2021;22(4):738. http://doi.org/10.3892/ol.2021.12999 PMid:34466150 DOI: https://doi.org/10.3892/ol.2021.12999

Merrill ML, Harper R, Birnbaum LS, Cardiff RD, Threadgill DW. Maternal dioxin exposure combined with a diet high in fat increases mammary cancer incidence in mice. Environ Health Perspect. 2010;118(5):596. http://doi.org/10.1289/ehp.0901047 PMid:20435547 DOI: https://doi.org/10.1289/ehp.0901047

Intagliata E, Gangi S, Trovato C, Vecchio R, Strazzanti A. Benign adenomyoepitelioma of the breast: Presentation of two rare cases and review of literature. Int J Surg Case Rep. 2020;67:1-4. http://doi.org/10.1016/J.IJSCR.2020.01.010 PMid:31991375 DOI: https://doi.org/10.1016/j.ijscr.2020.01.010

O’Neil M, Fan F, Damjanov I. Adenomyoepithelioma of the preast. Lab Med. 2008;39(8):477-80. http://doi.org/10.1309/L344VB54H1A9QA8K PMid:23627458 DOI: https://doi.org/10.1309/L344VB54H1A9QA8K

Cheng Z, Han T, Zhang X, Li X, Li H, Gu J. Prognostic factors for breast cancer squamous cell carcinoma and nomogram development for prediction: Population-based research. Transl Cancer Res. 2019;8(5):2014-23. http://doi.org/10.21037/tcr.2019.09.13 DOI: https://doi.org/10.21037/tcr.2019.09.13

Costa I, Solanas M, Escrich E. Histopathologic characterization of mammary neoplastic lesions induced with 7,12 dimethylbenz(alpha) anthracene in the rat: A comparative analysis with human breast tumors. Arch Pathol Lab Med. 2002;126(8):915-27. http://doi.org/10.5858/2002-126-0915-HCOMNL PMid:12171489 DOI: https://doi.org/10.5858/2002-126-0915-HCOMNL

Carraro DM, Elias EV, Andrade VP. Ductal carcinoma in situ of the breast: Morphological and molecular features implicated in progression. Biosci Rep. 2014;34(1):19-28. http://doi.org/10.1042/BSR20130077 PMid:27919043 DOI: https://doi.org/10.1042/BSR20130077

Lopes AC, Cova TF, Pais AA, Pereira JL, Colaç B, Cabrita AM. Improving discrimination in the grading of rat mammary tumors using two-dimensional mapping of histopathological observations. Exp Toxicol Pathol. 2014;66(1):73-80. http://doi.org/10.1016/j.etp.2013.09.001 PMid:24168877 DOI: https://doi.org/10.1016/j.etp.2013.09.001

Atif N. Role of immunohistochemical markers in breast cancer and their correlation with grade of tumour, our experience. Int Clin Pathol J. 2020;6(3):141-5. http://doi.org/10.15406/icpjl.2018.06.00175 DOI: https://doi.org/10.15406/icpjl.2018.06.00175

Furqan M, Pohan PU. Relationship of histopathology grading with molecular subtypes of breast cancer patients in Haji Adam Malik General Hospital 2016-2018. Scr SCORE. Sci Med J. 2020;2(1):28-37. http://doi.org/10.32734/scripta.v2i1.3364 DOI: https://doi.org/10.32734/scripta.v2i1.3364

Rakha EA, El-Sayed ME, Lee AH, Elston CW, Grainge MJ, Hodi Z. Prognostic significance of Nottingham histologic grade in invasive breast carcinoma. J Clin Oncol. 2008;26(19):3153-8. http://doi.org/10.1200/JCO.2007.15.5986 PMid:18490649 DOI: https://doi.org/10.1200/JCO.2007.15.5986

Cheun JH, Jung J, Lee ES, Rhu J, Lee HB, Lee KH, et al. Intensity of metastasis screening and survival outcomes in patients with breast cancer. Sci Rep. 2021;11(1):2851. http://doi.org/10.1038/s41598-021-82485-w PMid:33531549 DOI: https://doi.org/10.1038/s41598-021-82485-w

Narisuari ID, Manuaba IB. Prevalence and characteristics of breast cancer patients at the surgical oncology polyclinic of Sanglah Hospital, Bali, Indonesia in 2016. Int Sains Med. 2020;11(1):183-9. http://doi.org/10.15562/ism.v11i1.526 DOI: https://doi.org/10.15562/ism.v11i1.526

Feng M, Feng C, Yu Z, Fu Q, Ma Z, Wang F, et al. Histopathological alterations during breast carcinogenesis in a rat model induced by estrogen-progestogen combinations. Int J Clin Exp Med. 2015;8(1):346-57. PMid:25785005

Gallo D, Ferrandina G, Giacomelli S, Fruscella E, Zannoni GF, Morazzoni P, et al. Dietary soy modulation of biochemical parameters in DMBA-induced mammary tumors. Cancer Lett. 2002;186(1):43-8. http://doi.org/10.1016/s0304-3835(02)00326-9 PMid:12183074 DOI: https://doi.org/10.1016/S0304-3835(02)00326-9

Fragomeni SM, Sciallis A, Jeruss JS. Molecular subtypes and local-regional control of breast cancer Simona. Surg Oncol Clin North Am. 2018;27(1):95-120. http://doi.org/10.1016/j.soc.2017.08.005 PMid:29132568 DOI: https://doi.org/10.1016/j.soc.2017.08.005

Zhao JA, Chen JJ, Ju YC, Wu JH, Geng CZ, Yang HC. The effect of childbirth on carcinogenesis of DMBA-induced breast cancer in female SD rats. Chin J Cancer. 2011;30(11):779-85. http://doi.org/10.5732/cjc.011.10098 PMid:22035859 DOI: https://doi.org/10.5732/cjc.011.10098

Varga Z, Noske A, Ramach C, Padberg B, Moch H. Assessment of HER2 status in breast cancer: Overall positivity rate and accuracy by fluorescence in situ hybridization and immunohistochemistry in a single institution over 12 years: A quality control study. BMC Cancer. 2013;13:615. http://doi.org/10.1186/1471-2407-13-615 PMid:24377754 DOI: https://doi.org/10.1186/1471-2407-13-615

Sheikhpour E, Taghipour S. The differences of age, tumor grade, and Her2 amplification in Estrogen and progesterone receptor status in patients with breast cancer. Int J Cancer Manag. 2018;11(8):8-11. http://doi.org/10.5812/ijcm.9492 DOI: https://doi.org/10.5812/ijcm.9492

Nanto SS, Muhartono, Wulan AJ. Role of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) to predict breast cancer clinical stage. J Agromed Unila. 2017;4(2):256-9.

Ma Z, Kim YM, Howard EW, Feng X, Kosanke SD, Yang S, et al. DMBA promotes ErbB2mediated carcinogenesis via ErbB2 and estrogen receptor pathway activation and genomic instability. Oncol Rep. 2018;40(3):1632-40. http://doi.org/10.3892/or.2018.6545 PMid:30015966 DOI: https://doi.org/10.3892/or.2018.6545

Arnetha TS, Hernowo BS, Adha MJ, Rezano A. Relationship between molecular subtypes and overall survival of breast cancer in Bandung. Biomed Pharmacol J. 2020;13(3):1543-48. https://doi.org/10.13005/bpj/2028 DOI: https://doi.org/10.13005/bpj/2028

Kanyilmaz G, Yavuz BB, Aktan M, Karaagac M, Uyar M, Findik S. Prognostic importance of Ki-67 in breast cancer and its relationship with other prognostic factors. Eur J Breast Heal. 2019;15(4):256-61. http://doi.org/10.5152/ejbh.2019.4778 PMid:31620685 DOI: https://doi.org/10.5152/ejbh.2019.4778

Kermani TA, Kermani IA, Faham Z, Dolatkhah R. Ki-67 status in patients with primary breast cancer and its relationship with other prognostic factors. Biomed Res Ther. 2019;6(2):2986-91. http://doi.org/10.15419/bmrat.v6i2.520 PMid:23674192 DOI: https://doi.org/10.15419/bmrat.v6i2.520

Hashmi AA, Hashmi KA, Irfan M, Khan SM, Edhi MM, Ali JP, et al. Ki67 index in intrinsic breast cancer subtypes and its association with prognostic parameters. BMC Res. 2019;12(1):605. http://doi.org/10.1186/s13104-019-4653-x PMid:31547858 DOI: https://doi.org/10.1186/s13104-019-4653-x

Currier N, Solomon SE, Demicco EG, Chang DLF, Farago M, Ying H, et al. Oncogenic signaling pathways activated in DMBA-induced mouse mammary tumors. Toxicol Pathol. 2005;33(6):726-37. http://doi.org/10.1080/01926230500352226 PMid:16263698 DOI: https://doi.org/10.1080/01926230500352226

Asri A, Mayorita P, Khambri D. Relationship of ki-67 expression with histopathological characteristics in triple negative breast cancer. Maj Kedokt Andalas. 2015;38(3):165-72. DOI: https://doi.org/10.22338/mka.v38i3.318

Sen TA, Poe J, Yeong S, Peng C, Lai T, Hui C, et al. The role of Ki-67 in Asian triple negative breast cancers: A novel combinatory panel approach. Virchows Arch. 2019;475(6):709-25. http://doi.org/10.1007/s00428-019-02635-4 PMid:31407032 DOI: https://doi.org/10.1007/s00428-019-02635-4

Wu Q, Ma G, Deng Y, Luo W, Zhao Y, Li W, et al. Prognostic value of ki-67 in patients with resected triple-negative breast cancer: A meta-analysis. Front Oncol Front. 2019;9:1068. http://doi.org/10.3389/FONC.2019.01068 PMid:31681601 DOI: https://doi.org/10.3389/fonc.2019.01068

Downloads

Published

2022-01-18

How to Cite

1.
Fidianingsih I, Aryandono T, Widyarini S, Herwiyanti S. Profile of Histopathological Type and Molecular Subtypes of Mammary Cancer of DMBA-induced Rat and its Relevancy to Human Breast Cancer. Open Access Maced J Med Sci [Internet]. 2022 Jan. 18 [cited 2024 Jun. 19];10(A):71-8. Available from: https://oamjms.eu/index.php/mjms/article/view/7975

Most read articles by the same author(s)