Abstract
Tamoxifen (TAM) is an accredited drug used for treatment and prevention of breast cancer. Due to the long-term taking and the trend for women to delay childbearing, inadvertent conception occasionally occurs during TAM treatment. To explore the effects of TAM on a fetus, pregnant mice at gestation day 16.5 were orally administrated with different concentrations of TAM. Molecular biology techniques were used to analyze the effects of TAM on primordial follicle assembly of female offspring and the mechanism. It was found that maternal TAM exposure affected primordial follicle assembly and damaged the ovarian reserve in 3 dpp offspring. Up to 21 dpp, the follicular development had not recovered, with significantly decreased antral follicles and decreased total follicle number after maternal TAM exposure. Cell proliferation was significantly inhibited; however, the cell apoptosis was induced by maternal TAM exposure. Epigenetic regulation was also involved in the process of TAM induced abnormal primordial follicle assembly. The changed levels of H3K4me3, H3K9me3, and H3K27me3 presented the function of histone methylation in the regulation of the effects of maternal TAM exposure on the reproduction of female offspring. Moreover, the changed level of RNA m6A modification and the changed expression of genes related to transmethylation and demethylation proved the role of m6A in the process. Maternal TAM exposure led to abnormal primordial follicle assembly and follicular development by affecting cell proliferation, cell apoptosis, and epigenetics.
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References
Amant F, Loibl S, Neven P, Van Calsteren K (2012) Breast cancer in pregnancy. Lancet 379(9815):570–579. https://doi.org/10.1016/S0140-6736(11)61092-1
Barthelmes L, Gateley CA (2004) Tamoxifen and pregnancy. Breast 13(6):446–451. https://doi.org/10.1016/j.breast.2004.08.007
Black JC, Van Rechem C, Whetstine JR (2012) Histone lysine methylation dynamics: establishment, regulation, and biological impact. Mol Cell 48(4):491–507. https://doi.org/10.1016/j.molcel.2012.11.006
Breckwoldt M, Karck U (2000) Tamoxifen for breast cancer prevention. Exp Clin Endocrinol Diabetes 108(4):243–246. https://doi.org/10.1055/s-2000-7751
Cersosimo RJ (2003) Tamoxifen for prevention of breast cancer. Ann Pharmacother 37(2):268–273. https://doi.org/10.1177/106002800303700219
Chamness GC, Bannayan GA, Landry LA Jr, Sheridan PJ, McGuire WL (1979) Abnormal reproductive development in rats after neonatally administered antiestrogen (tamoxifen). Biol Reprod 21(5):1087–1090. https://doi.org/10.1095/biolreprod21.5.1087
Clark JH, McCormack S (1977) Clomid or nafoxidine administered to neonatal rats causes reproductive tract abnormalities. Science 197(4299):164–165. https://doi.org/10.1126/science.877546
Diwan BA, Anderson LM, Ward JM (1997) Proliferative lesions of oviduct and uterus in CD-1 mice exposed prenatally to tamoxifen. Carcinogenesis 18(10):2009–2014. https://doi.org/10.1093/carcin/18.10.2009
Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N (1998) Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 90(18):1371–1388. https://doi.org/10.1093/jnci/90.18.1371
Haque MM, Desai KV (2019) Pathways to endocrine therapy resistance in breast cancer. Front Endocrinol (lausanne) 10:573. https://doi.org/10.3389/fendo.2019.00573
Huang H, Weng H, Zhou K, Wu T, Zhao BS, Sun M, Chen Z, Deng X, Xiao G, Auer F, Klemm L, Wu H, Zuo Z, Qin X, Dong Y, Zhou Y, Qin H, Tao S, Du J, Liu J, Lu Z, Yin H, Mesquita A, Yuan CL, Hu YC, Sun W, Su R, Dong L, Shen C, Li C, Qing Y, Jiang X, Wu X, Sun M, Guan JL, Qu L, Wei M, Muschen M, Huang G, He C, Yang J, Chen J (2019) Histone H3 trimethylation at lysine 36 guides m(6)A RNA modification co-transcriptionally. Nature 567(7748):414–419. https://doi.org/10.1038/s41586-019-1016-7
Hwang JJ, Kim HN, Kim J, Cho DH, Kim MJ, Kim YS, Kim Y, Park SJ, Koh JY (2010) Zinc(II) ion mediates tamoxifen-induced autophagy and cell death in MCF-7 breast cancer cell line. Biometals 23(6):997–1013. https://doi.org/10.1007/s10534-010-9346-9
Iguchi T, Hirokawa M, Takasugi N (1986) Occurrence of genital tract abnormalities and bladder hernia in female mice exposed neonatally to tamoxifen. Toxicology 42(1):1–11. https://doi.org/10.1016/0300-483x(86)90087-9
Ishizuka S, Satou S (2016) A case of delivery of healthy infant in breast cancer patient incidentally treated with goserelin acetate and tamoxifen during pregnancy. Breast Cancer 23(1):164–166. https://doi.org/10.1007/s12282-013-0469-z
Jordan VC (2003) Tamoxifen: a most unlikely pioneering medicine. Nat Rev Drug Discov 2(3):205–213. https://doi.org/10.1038/nrd1031
Katzenellenbogen BS, Montano MM, Ediger TR, Sun J, Ekena K, Lazennec G, Martini PG, McInerney EM, Delage-Mourroux R, Weis K, Katzenellenbogen JA (2000) Estrogen receptors: selective ligands, partners, and distinctive pharmacology. Recent Prog Horm Res 55:163–193 (discussion 194-165)
Koca E, Kuzan TY, Babacan T, Turkbeyler IH, Furkan S, Altundag K (2013) Safety of tamoxifen during pregnancy: 3 case reports and review of the literature. Breast Care (basel) 8(6):453–454. https://doi.org/10.1159/000357321
Li F, Chen S, Yu J, Gao Z, Sun Z, Yi Y, Long T, Zhang C, Li Y, Pan Y, Qin C, Long W, Liu Q, Zhao W (2021) Interplay of m(6) A and histone modifications contributes to temozolomide resistance in glioblastoma. Clin Transl Med 11(9):e553. https://doi.org/10.1002/ctm2.553
Ma G, He J, Yu Y, Xu Y, Yu X, Martinez J, Lonard DM, Xu J (2015) Tamoxifen inhibits ER-negative breast cancer cell invasion and metastasis by accelerating Twist1 degradation. Int J Biol Sci 11(5):618–628. https://doi.org/10.7150/ijbs.11380
Manna S, Holz MK (2016) Tamoxifen action in ER-negative breast cancer. Sign Transduct Insights 5:1–7. https://doi.org/10.4137/STI.S29901
McCormack S, Clark JH (1979) Clomid administration to pregnant rats causes abnormalities of the reproductive tract in offspring and mothers. Science 204(4393):629–631. https://doi.org/10.1126/science.432668
Moon AS, Dorigo O (2021) Long-term efficacy of megestrol acetate and tamoxifen in a recurrent adult granulosa cell tumor of the ovary. Gynecol Oncol Rep 36:100770. https://doi.org/10.1016/j.gore.2021.100770
Nishiyama S, Hayashi S, Abe N, Kira S, Oda M, Lee L, To Y, Goto M, Tsujioka H (2022) Bilateral ovarian endometriomas after laparoscopic hysterectomy following adjuvant tamoxifen therapy for breast cancer: a case report. Case Rep Womens Health 36:e00442. https://doi.org/10.1016/j.crwh.2022.e00442
Olcina MM, Leszczynska KB, Senra JM, Isa NF, Harada H, Hammond EM (2016) H3K9me3 facilitates hypoxia-induced p53-dependent apoptosis through repression of APAK. Oncogene 35(6):793–799. https://doi.org/10.1038/onc.2015.134
Osborne CK (1998) Tamoxifen in the treatment of breast cancer. N Engl J Med 339(22):1609–1618. https://doi.org/10.1056/NEJM199811263392207
Pappa S, Padilla N, Iacobucci S, Vicioso M, Alvarez de la Campa E, Navarro C, Marcos E, de la Cruz X, Martinez-Balbas MA (2019) PHF2 histone demethylase prevents DNA damage and genome instability by controlling cell cycle progression of neural progenitors. Proc Natl Acad Sci USA 116(39):19464–19473. https://doi.org/10.1073/pnas.1903188116
Prado F, Jimeno-Gonzalez S, Reyes JC (2017) Histone availability as a strategy to control gene expression. RNA Biol 14(3):281–286. https://doi.org/10.1080/15476286.2016.1189071
Robinson E, Kimmick GG, Muss HB (1996) Tamoxifen in postmenopausal women a safety perspective. Drugs Aging 8(5):329–337. https://doi.org/10.2165/00002512-199608050-00002
Seyedoshohadaei F, Zandvakily F, Shahgeibi S (2012) Comparison of the effectiveness of clomiphene citrate, tamoxifen and letrozole in ovulation induction in infertility due to isolated unovulation. Iran J Reprod Med 10(6):531–536
Shagufta AI (2018) Tamoxifen a pioneering drug: An update on the therapeutic potential of tamoxifen derivatives. Eur J Med Chem 143:515–531. https://doi.org/10.1016/j.ejmech.2017.11.056
Stillman B (2018) Histone modifications: insights into their influence on gene expression. Cell 175(1):6–9. https://doi.org/10.1016/j.cell.2018.08.032
Tewari K, Bonebrake RG, Asrat T, Shanberg AM (1997) Ambiguous genitalia in infant exposed to tamoxifen in utero. Lancet 350(9072):183. https://doi.org/10.1016/S0140-6736(97)24029-8
Torres-Lopez L, Maycotte P, Linan-Rico A, Linan-Rico L, Donis-Maturano L, Delgado-Enciso I, Meza-Robles C, Vasquez-Jimenez C, Hernandez-Cruz A, Dobrovinskaya O (2019) Tamoxifen induces toxicity, causes autophagy, and partially reverses dexamethasone resistance in Jurkat T cells. J Leukoc Biol 105(5):983–998. https://doi.org/10.1002/JLB.2VMA0818-328R
Wei J, Yu X, Yang L, Liu X, Gao B, Huang B, Dou X, Liu J, Zou Z, Cui XL, Zhang LS, Zhao X, Liu Q, He PC, Sepich-Poore C, Zhong N, Liu W, Li Y, Kou X, Zhao Y, Wu Y, Cheng X, Chen C, An Y, Dong X, Wang H, Shu Q, Hao Z, Duan T, He YY, Li X, Gao S, Gao Y, He C (2022a) FTO mediates LINE1 m(6)A demethylation and chromatin regulation in mESCs and mouse development. Science 376(6596):968–973. https://doi.org/10.1126/science.abe9582
Wei W, Komatsu K, Osuka S, Murase T, Bayasula B, Nakanishi N, Nakamura T, Goto M, Iwase A, Masubuchi S, Kajiyama H (2022b) Tamoxifen activates dormant primordial follicles in mouse ovaries. Reprod Sci 29(12):3404–3412. https://doi.org/10.1007/s43032-022-00896-0
Wen L, Chen Y, Zeng LL, Zhao F, Yi S, Yang LJ, Zhang BP, Zhao J, Zhao ZC, Zhang C (2015) Triptolide induces cell apoptosis by targeting h3k4me3 and downstream effector proteins in KM3 multiple myeloma cells. Curr Pharm Biotechnol 17(2):147–160. https://doi.org/10.2174/1389201016666150930115555
Weng SC, Kashida Y, Kulp SK, Wang D, Brueggemeier RW, Shapiro CL, Chen CS (2008) Sensitizing estrogen receptor-negative breast cancer cells to tamoxifen with OSU-03012, a novel celecoxib-derived phosphoinositide-dependent protein kinase-1/Akt signaling inhibitor. Mol Cancer Ther 7(4):800–808. https://doi.org/10.1158/1535-7163.MCT-07-0434
Wickerham DL, Costantino JP, Vogel VG, Cronin WM, Cecchini RS, Ford LG, Wolmark N (2009) The use of tamoxifen and raloxifene for the prevention of breast cancer. Recent Results Cancer Res 181:113–119. https://doi.org/10.1007/978-3-540-69297-3_12
Wu SY, Sharma S, Wu K, Tyagi A, Zhao D, Deshpande RP, Watabe K (2021) Tamoxifen suppresses brain metastasis of estrogen receptor-deficient breast cancer by skewing microglia polarization and enhancing their immune functions. Breast Cancer Res 23(1):35. https://doi.org/10.1186/s13058-021-01412-z
Yan N, Xu L, Wu X, Zhang L, Fei X, Cao Y, Zhang F (2017) GSKJ4, an H3K27me3 demethylase inhibitor, effectively suppresses the breast cancer stem cells. Exp Cell Res 359(2):405–414. https://doi.org/10.1016/j.yexcr.2017.08.024
Zahreddine R, Davezac M, Smirnova N, Buscato M, Lhuillier E, Lupieri A, Solinhac R, Vinel A, Vessieres E, Henrion D, Renault MA, Gadeau AP, Flouriot G, Lenfant F, Laffargue M, Metivier R, Arnal JF, Fontaine C (2020) Tamoxifen accelerates endothelial healing by targeting ERalpha in smooth muscle cells. Circ Res 127(12):1473–1487. https://doi.org/10.1161/CIRCRESAHA.120.317062
Zhang Y, Sun Z, Jia J, Du T, Zhang N, Tang Y, Fang Y, Fang D (2021) Overview of histone modification. Adv Exp Med Biol 1283:1–16. https://doi.org/10.1007/978-981-15-8104-5_1
Acknowledgements
This work was supported by the Key Research and Development Program of Shandong Province (2021LZGC001), Taishan Scholar Foundation of Shandong Province of China (ts20190946) and Natural Science Foundation of Shandong Province, China (ZR2017MC033).
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All authors contributed to the study conception and design. Material preparation was performed by J.Z., J.Z., and R.W. Data collection and analysis were performed by Y.S. and D.S. The experiments were designed by W.S. and X.S. The first draft of the manuscript was written by X.S. All authors reviewed the manuscript.
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418_2023_2196_MOESM1_ESM.tif
Fig S1: Maternal TAM exposure changed the serum levels of E2. (a) TAM serum concentrations in orally administered TAM mice detected by ELISA. (b) Serum levels of E2 detected by ELISA (TIF 2095 KB)
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Zhao, J., Zhang, J., Sun, Y. et al. Maternal tamoxifen exposure leads to abnormal primordial follicle assembly. Histochem Cell Biol 160, 97–111 (2023). https://doi.org/10.1007/s00418-023-02196-3
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DOI: https://doi.org/10.1007/s00418-023-02196-3