Abstract
Mammary gland hyperplasia is one of the risk factors for breast cancer. Till date, there is no study that has addressed the effect of hemin in this condition. Thus, this study was designed to evaluate the effect of the heme oxygenase 1 (HO-1) inducer (hemin) and its inhibitor (zinc protoporphyrin-IX) (ZnPP-IX) on mammary gland hyperplasia (MGH) induced by estrogen and progesterone in adult albino rats. Forty adult female albino rats were divided into the control group, MGH group, MGH + Hemin group, and MGH + Hemin + ZnPP-IX group. Serum levels of estradiol and progesterone were measured. Breast tissues were taken for estimation of oxidative, inflammatory, and apoptotic markers. Mammary gland histology was performed, and expression of Ki-67, Beclin, and P53 in breast tissue was also measured. Estrogen and progesterone administration induced hyperplasia of cells lining the ducts of the breast tissues associated with increased diameter and height of the nipples as well as increased oxidative stress markers, inflammatory markers, antiapoptotic markers, and cell autophagy. Hemin administration during induction of MGH can reverse all the affected parameters. Then, these effects were abolished by ZnPP-IX administration. We concluded that hemin administration can antagonize the cell stress induced by estrogen and progesterone and protect against the development of mammary gland hyperplasia via modulation of Nrf2/HO-1 and NF-κB pathways.
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The data that support the findings of this study are available on request from the corresponding author.
References
Abdel-Hakeem EA, Abdel Hafez SMN, Kamel BA, Abdel-Hamid HA (2022) Angiotensin 1–7 mitigates rhabdomyolysis induced renal injury in rats via modulation of TLR-4/NF-kB/iNOS and Nrf-2/heme-oxygenase-1 signaling pathways. Life Sci 5(303):120678
Al-Dhaheri W, Hassouna I, Karam SM (2018) Genetic polymorphisms and protein expression of P53 and BRCA1 in preneoplastic and neoplastic rat mammary glands. Oncol Rep 39:2193–2200
Becks L, Prince M, Burson H, Christophe C, Broadway M, Itoh K, Yamamoto M, Mathis M, Orchard E, Shi R (2010) Aggressive mammary carcinoma progression in Nrf2 knockout mice treated with 7, 12-dimethylbenz [a] anthracene. BMC Cancer 10:1–17
Bostanci Z, Mack Jr RP, Lee S, Soybel DI, Kelleher SLJRT (2015) Paradoxical zinc toxicity and oxidative stress in the mammary gland during marginal dietary zinc deficiency 54:84-92
Buchwalow IB, Böcker W (2010) Immunohistochemistry: basics and methods. Springer Science & Business Media, pp 109–127
Chi X, Guo N, Yao W, Jin Y, Gao W, Cai J, Hei ZJJOTM (2016) Induction of heme oxygenase-1 by hemin protects lung against orthotopic autologous liver transplantation-induced acute lung injury in rats. J Transl Med 2(14):35
Collino M, Pini A, Mugelli N, Mastroianni R, Bani D, Fantozzi R, Papucci L, Fazi M, Masini E (2013) Beneficial effect of prolonged heme oxygenase 1 activation in a rat model of chronic heart failure. Dis Model Mech 6:1012–1020
Gandini NA, Alonso EN, Fermento ME, Mascaró M, Abba MC, Coló GP, Arévalo J, Ferronato MJ, Guevara JA, Núñez M (2019) Heme oxygenase-1 has an antitumor role in breast cancer. Antioxid Redox Signal 30:2030–2049
Gewirtz DA (2014) The four faces of autophagy: implications for cancer therapyautophagy and cancer therapy. Can Res 74:647–651
Gu L, Xu Q, Liu H, Xie J, Zhang LJBR (2018) MicroRNA array analysis of the regulation of microRNAs in rats exhibiting hyperplasia of mammary glands 9:142-146
Ibrahim MFG, Allam FAFA (2022) Potential stem cell—conditioned medium and their derived exosomes versus omeprazole in treatment of experimental model of gastric ulcer. Acta Histochem 124:151896
Jagadeesh ASV, Fang X, Kim SH, Guillen-Quispe YN, Zheng J, Surh Y-J, Kim S-J (2022) Non-canonical vs. canonical functions of heme oxygenase-1 in cancer. J Cancer Prevent 27:7
Jang H-Y, Hong O-Y, Chung E-Y, Park K-H, Kim J-S (2020) Roles of JNK/Nrf2 pathway on hemin-induced heme oxygenase-1 activation in MCF-7 human breast cancer cells. Medicina 56:268
Jung S, Jeong H, Yu S-W (2020) Autophagy as a decisive process for cell death. Exp Mol Med 52:921–930
Kaluzki I, Hailemariam-Jahn T, Doll M, Kaufmann R, Balermpas P, Zöller N, Kippenberger S, Meissner M (2019) Dimethylfumarate inhibits colorectal carcinoma cell proliferation: evidence for cell cycle arrest, apoptosis and autophagy. Cells 8:1329
Kim J-H, Kim KM, Jeong JU, Shin JH, Shin JM, Bang KT (2019) Nrf2-Heme oxygenase-1 modulates autophagy and inhibits apoptosis triggered by elevated glucose levels in renal tubule cells. Kidney Res Clin Pract 38:318
Lakritz JR, Poutahidis T, Levkovich T, Varian BJ, Ibrahim YM, Chatzigiagkos A, Mirabal S, Alm EJ, Erdman SE (2014) Beneficial bacteria stimulate host immune cells to counteract dietary and genetic predisposition to mammary cancer in mice. Int J Cancer 135:529–540
Li Q, Liang S, Lai Q, Shen L, Zhang Y, Guo R (2021a) Heme oxygenase-1 alleviates advanced glycation end product-induced oxidative stress, inflammatory response and biological behavioral disorders in rat dermal fibroblasts. Exp Ther Med 22:1–11
Li W, Zhao L, Li Y, Zhai Z (2021) Artesunate attenuates proliferation of epithelial cells by downregulating the NF-κB and AKT signaling pathways in benign mammary gland hyperplasia rats. Annals Trans Med 9(10):848
Lim H-S, Jin S, Yun SJ (2016) Modulation of melanogenesis by heme oxygenase-1 via p53 in normal human melanocytes. Chonnam Med J 52:45–52
Liu J, Zhang J-F, Gong G-H, Zhang B, Wei C-X (2020) Therapeutic effect of mongolian medicine RuXian-I on hyperplasia of mammary gland induced by estrogen/progesterone through CRYAB-promoted apoptosis. Evid-Based Complement Altern Med 27(2020):5707106
Liu Y, Wu D, Wang K, Chen H, Xu H, Zong W, Zhang N, Zhao L, Lin Z, Ji T (2022) Dose-dependent effects of royal jelly on estrogen-and progesterone-induced mammary gland hyperplasia in rats. Mol Nutr Food Res 66:2100355
Lu J-J, Abudukeyoumu A, Zhang X, Liu L-B, Li M-Q, Xie F (2021) Heme oxygenase 1: a novel oncogene in multiple gynecological cancers. Int J Biol Sci 17:2252
Luu Hoang KN, Anstee JE, Arnold JN (2021) The diverse roles of heme oxygenase-1 in tumor progression. Front Immunol 12:658315
Mahawar L, Popek R, Shekhawat GS, Alyemeni MN, Ahmad P (2021) Exogenous hemin improves Cd2+ tolerance and remediation potential in Vigna radiata by intensifying the HO-1 mediated antioxidant defence system. Sci Rep 11:1–12
Mense SM, Remotti F, Bhan A, Singh B, El-Tamer M, Hei TK, Bhat HK (2008) Estrogen-induced breast cancer: alterations in breast morphology and oxidative stress as a function of estrogen exposure. Toxicol Appl Pharmacol 232:78–85
Ngo V, Duennwald MLJA (2022) Nrf2 and oxidative stress: a general overview of mechanisms and implications in human disease 11:2345
Nitti M, Ivaldo C, Traverso N, Furfaro AL (2021) Clinical significance of heme oxygenase 1 in tumor progression. Antioxidants 10:789
Park C, Cha H-J, Lee H, Kim G-Y, Choi YH (2021) The regulation of the TLR4/NF-κB and Nrf2/Ho-1 signaling pathways is involved in the inhibition of lipopolysaccharide-induced inflammation and oxidative reactions by morroniside in RAW 264.7 macrophages. Arch Biochem Biophysics 706:108926
Park S-A, Lee M-H, Na H-K, Surh Y-J (2019) Correction: 4-hydroxyestradiol induces mammary epithelial cell transformation through Nrf2-mediated heme oxygenase-1 overexpression. Oncotarget 10:1266
Poncin A, Onesti CE, Josse C, Boulet D, Thiry J, Bours V, Jerusalem G (2021) Immunity and breast cancer: focus on eosinophils. Biomedicines 9:1087
Qiao X, Wang B, Yuan Z, Yu F, Zhang Y, Wang Y, Yang Y, Tang J, Jiang Z, Lin L (2022) The polysaccharides from Yiqi Yangyin complex attenuated mammary gland hyperplasia: integrating underlying biological mechanisms and network pharmacology. J Funct Foods 88:104878
Satoh H, Moriguchi T, Saigusa D, Baird L, Yu L, Rokutan H, Igarashi K, Ebina M, Shibata T, Yamamoto M (2016) NRF2 intensifies host defense systems to prevent lung carcinogenesis, but after tumor initiation accelerates malignant cell growthgenetic Nrf2 activation in chemical lung carcinogenesis. Can Res 76:3088–3096
Shah R (2014) Estrogen differentially regulates expression of P-38 and hemeoxygenase-1 in mouse cervix. Chron New Res 1:1–7
Song D, Shi X, Li C, Cao X, Lu Y, Li J (2022) Effect of vitamin D3 on hyperplasia of mammary glands in experimental rats. Gland Surg 11:136–146
Suvarna KS, Layton C, Bancroft JD (2018) Bancroft’s theory and practice of histological techniques E-Book. Elsevier Health Sciences 1:573
Tao L, Xiang D, Xie Y, Bronson RT, Li Z (2017) Induced p53 loss in mouse luminal cells causes clonal expansion and development of mammary tumours. Nat Commun 8:1–13
Vanguilder HD, Vrana KE, Freeman WMJB (2008) Twenty-five years of quantitative PCR for gene expression analysis 44:619-626
Wang Y, Wei S, Gao T, Yang Y, Lu X, Zhou X, Li H, Wang T, Qian L, Zhao Y (2018) Anti-inflammatory effect of a TCM formula Li-Ru-Kang in rats with hyperplasia of mammary gland and the underlying biological mechanisms. Front Pharmacol 9:1318
Wu S, Lu H, Bai Y (2019) Nrf2 in cancers: a double-edged sword. Cancer Med 8:2252–2267
Xie Q, Liu Y, Li X (2020) The interaction mechanism between autophagy and apoptosis in colon cancer. Transl Oncol 13:100871
Yang H, Zhang L, Chen J, Zhang X, Zhao Z, Zhao LJC (2022) Medicine MMI (2022) Heme oxygenase-1 inhibits the proliferation of hepatic stellate cells by activating PPARγ and suppressing NF-κB. Comput Math Methods Med 2022:8920861
You Z, Sun J, Xie F, Chen Z, Zhang S, Chen H, Liu F, Li L, Chen G, Song YJOM, Longevity C (2017) Modulatory effect of fermented papaya extracts on mammary gland hyperplasia induced by estrogen and progestin in female rats. Oxid Med Cell Longev 2017:8235069
Zawacka-Pankau JE (2022) The Role of p53 Family in cancer. Cancers (Basel) 14(3):823
Zhang J-F, Liu J, Gong G-H, Zhang B, Wei C-X (2019) Mongolian medicine RuXian-I treatment of estrogen-induced mammary gland hyperplasia in rats related to TCTP regulating apoptosis. Evid-Based Complement Altern Med 2019:1907263
Zheng T, Zhan J, Yang M, Wang M, Sun W, Shan Z, Chen H (2021) Hemin-induced increase in saponin content contributes to the alleviation of osmotic and cold stress damage to Conyza blinii in a heme oxygenase 1-dependent manner. J Zhejiang Univ-Sci B 22:682–694
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All authors are sincerely thankful for the exerted efforts of the technicians in the departments of Physiology and Histology, Faculty of Medicine, Minia University for their help during the accomplishment of this research.
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All authors agreed to take responsibility for the entire content of this manuscript and accepted its submission. Dr Heba A. Abdel-Hamid performed the research protocol, the experiment, results collection and analysis, and wrote the manuscript. Dr Manar Fouli Gaber Ibrahim performed, wrote, and analyzed the histopathology part and the immunohistochemistry sections. Dr Heba Marey performed and wrote the RT-PCR analysis. All authors revised the final version of the manuscript and agreed on its publication.
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Abdel-Hamid, H.A., Marey, H. & Ibrahim, M.F.G. Hemin protects against cell stress induced by estrogen and progesterone in rat mammary glands via modulation of Nrf2/HO-1 and NF-κB pathways. Cell Stress and Chaperones 28, 289–301 (2023). https://doi.org/10.1007/s12192-023-01337-w
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DOI: https://doi.org/10.1007/s12192-023-01337-w