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Effects of Estradiol, Progestogens, and of Tibolone on Breast Proliferation and Apoptosis

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Effects of Estradiol, Progestogens, and of Tibolone on Breast Proliferation and Apoptosis CLIMACTERIC 2015;18:518–522 Effects of estradiol, progestogens, and of tibolone on breast proliferation and apoptosis L. M. Pompei , E. P. Cunha , M. L. Steiner , T. R. Theodoro * , A. M. A. A. Mader † , G. Petri ‡ , M. A. S. Pinhal * and C. E. Fernandes Discipline of Gynecology of the Faculdade de Medicina do ABC; * Discipline of Biochemistry of the Faculdade de Medicina do ABC; † Discipline of Pathology of the Faculdade de Medicina do ABC; ‡ Vivarium of the Faculdade de Medicina do ABC, Santo Andr é , Brazil Key words: PROLIFERATION , APOPTOSIS, ESTROGEN , PROGESTOGENS , BREAST CANCER ABSTRACT Aim To study the effects of estrogen therapy, alone or combined with progestogens, and of tibolone on the expression of proliferation and apoptosis markers in normal breast tissue. Methods Thirty 250-day-old Wistar rats were castrated and 3 weeks later received one of the following treatments by gavage for 5 weeks: (1) estradiol benzoate; (2) estradiol benzoate ϩ medroxyprogesterone acetate; (3) estradiol benzoate ϩ norethisterone acetate; (4) estradiol benzoate ϩ dydrogesterone; (5) tibolone; (6) placebo. Following treatment, the expression of proliferating cell nuclear antigen (PCNA) and caspase-3 was analyzed by quantitative immunohistochemistry in the breast tissue, and proliferation and apoptosis were analyzed semiquantitatively by microscopic imaging. Results There was a statistically signifi cant difference among the groups for PCNA, caspase-3 and the caspase-3 : PCNA ratio. Tibolone was associated with the lowest proliferative activity, followed by estradiol benzoate ϩ dydrogesterone; however, estradiol benzoate ϩ dydrogesterone showed the greatest rate of apoptosis. Conclusions The various progestogens can have more or less proliferative and pro-apoptotic effects than estradiol alone. Among the treatment schemes analyzed, the estradiol ϩ dydrogesterone combination resulted For personal use only. in a higher apoptosis rate in relation to the proliferation rate and tibolone was associated with the lowest proliferation. INTRODUCTION Normal, non-neoplastic breast tissue has not been the focus of many studies, and no studies to our knowledge to date have Observational and randomized studies have shown that estro- compared the effects of various progestogens on proliferation gen and progestogen therapies following menopause increase and apoptosis in breast tissue, and this has raised the interest the risk of developing breast cancer to a greater extent than in studying such aspects. The aim of this study was to evaluate using estrogen alone 1,2 . However, it is possible that the various the effects of estrogen and progestogens, including tibolone, Climacteric Downloaded from informahealthcare.com by University Studi Di Torino on 07/02/15 progestogens can have different impacts on the risk of devel- on the expression of epithelial proliferation and apoptosis oping breast cancer 3 . markers in normal breast tissue of castrated rats. Breast cancer cell culture studies have shown that some synthetic progestogens induce a proliferative response, whilst others do not have this effect or it is less intense 4 . The interac- METHODS tion between estrogens and the various progestogens is certainly complex as is its involvement in the appearance of cancer; All of the procedures used in the study described below were however, the effects on epithelial proliferation and cell apopto- approved by the animal research ethics committee of the sis can be important mechanisms that are involved. The diverse Faculdade de Medicina do ABC. effects that hormonal treatments have on these parameters Thirty 250-day-old Wistar rats were randomly selected and have already been reported for breast cancer cell cultures 5 . subjected to bilateral oophorectomy, under anesthesia with Correspondence: Dr L. M. Pompei, Rua Dr. Procopio Ribeiro dos Santos, 84 S ã o Paulo, Brazil 04664-130; E-mail: [email protected] ORIGINAL ARTICLE Received 22-12-2014 © 2015 International Menopause Society Revised 13-02-2015 DOI: 10.3109/13697137.2015.1020482 Accepted 14-02-2015 Breast proliferation and apoptosis Pompei et al. ketamine and xylazine injected intraperitoneally. The ventral quantifi ed using the Scion ImageLab ® for Windows software longitudinal abdominal approach was used for identifying and (Scion Corporation, Frederick, USA). ligating the ovarian pedicles and then removing the gonads. A histological analysis of fi ve highly magnifi ed fi elds was Three weeks after the surgical procedure, microscopic also carried out by the same pathologist (A.M.M.), in a blind analysis of vaginal smears of all of the rats was carried out manner for treatment groups, with ductal epithelial prolifera- to confi rm hypoestrogenism. Subsequently, the animals were tion and apoptosis being classifi ed in a semiquantitative man- randomly divided into six groups of fi ve animals each, and ner as grade 0 (absent or minimal) to 3 (maximum). the groups received one of the following treatments admin- istered daily by gavage for 5 consecutive weeks: Group EB: estradiol benzoate (EB) administered orally in a dose of 1 mg/ Statistical analysis kg; Group EB/MPA: EB 1 mg/kg combined with medroxy- progesterone acetate (MPA) 0.2 mg/kg; Group EB/NETA: The data obtained were organized in electronic spreadsheets EB 1 mg/kg combined with norethisterone acetate (NETA) using the Microsoft Excel ® 2007 software (Microsoft Corpo- 0.2 mg/kg; Group EB/DI: EB 1 mg/kg combined with dydro- ration ® , San Diego, USA). Statistical analysis was carried out gesterone (DI) 2 mg/kg; Group TIB: tibolone (TIB) 1 mg/kg; using the software WinSTAT ® , version 2007.1 (R. Fitch Soft- Group CTR: oral placebo. ware, Germany). Continuous numerical data are presented in The animals were kept in a calm environment with a the mean ϩϪ standard deviation format. Normal distribution constant temperature of 23 ° C, a 12-h light period per day, was tested using the Kolmogorov – Smirnov test. Group com- and water and food ad libitum . parisons were carried out by analysis of variance (ANOVA) At 250 days of life, the fertility of female rats is declin- and multiple comparisons were corrected using the least ing; this is roughly comparable to the menopausal transition signifi cant difference method. The Kruskal – Wallis test was for women. A 5-week treatment corresponds to about eight carried out for ordinal numerical data (semiquantitative estrous cycles of this animal, roughly comparable to eight histological analysis) or data without a normal distribution, menstrual cycles in women. or when homogeneity of variance had not been proven. Spear- At the end of the treatment period, the rats were euthanized man rank correlation analysis was carried out for quantitative in a CO2 chamber. The second left thoracic mammary gland and semiquantitative parameters. A signifi cance level of 5% of each animal was immediately isolated, resected and fi xed was adopted. in 10% buffered formalin. The detailed procedures for the immunohistochemical analysis were the same as those previously published by RESULTS our group 6 . Briefl y, immunohistochemistry was carried out to analyze protein immunolabeling for proliferating cell A rat from the tibolone group was found dead one morning μ For personal use only. nuclear antigen (PCNA) and caspase-3 in 3- m-thick histo- with evidence of having been attacked by the other rats in the logical slices. The primary antibodies used were anti-PCNA group. Therefore information from 29 animals was analyzed. and anti-caspase-3 (Santa Cruz Biotechnology, Santa Cruz, The average weight of the rats were 310.6 ϩϪ 25.9 g at the USA) diluted in bovine serum albumin (BSA) in a ratio of 1 : beginning of the study. 300. The slides were analyzed using a Nikon Eclipse TS100 Table 1 shows the immunohistochemistry results for the optic microscope (Nikon Instruments, Melville, USA) using markers PCNA, caspase-3 and the caspase-3 : PCNA ratio for the same light intensity and condenser height for all slides. each group. It can be noted that there was a statistically sig- The areas that best represented the immunolabeling of the nifi cant difference for all parameters. In multiple comparisons, slide were always chosen by the same pathologist (A.M.M.), statistically signifi cant differences were found amongst all the in a blind manner for treatment groups, and analyzed by groups for PCNA, with the exception of the comparison for 400 ϫ magnifi cation. Photomicrographs (640 ϫ 480 pixels) EB versus EB/NETA. In the case of caspase-3 expression, the Climacteric Downloaded from informahealthcare.com by University Studi Di Torino on 07/02/15 of consecutive, non-overlapping fi elds were obtained using a majority of comparisons amongst the groups was statistically Nikon Coolpix 4300 (Nikon Corporation, Japan) digital cam- signifi cant, with the exception of CTR vs. EB, CTR vs. EB/MPA, era with maximum zoom. Immunohistochemical labeling was CTR vs. EB/NETA, EB vs. EB/MPA and EB/NETA vs. EB/DI. Table 1 Results of the immunohistochemistry quantifi cation of proliferating cell nuclear antigen (PCNA), caspase-3 and the caspase-3 : PCNA ratio, according to treatment group Estradiol Estradiol Estradiol Estradiol benzoate benzoate benzoate ϩ MPA benzoate ϩ NETA ϩ dydrogesterone Tibolone Control p Value PCNA 62.8 ϩϪ 4.8 87.8 ϩϪ 7.1 64.0 ϩϪ 8.1 40.8 ϩϪ 3.3 28.1 ϩϪ 4.2 118.4 ϩϪ 3.5 Ͻ 0.001 Caspase-3 78.1 ϩϪ 10.6 81.5 ϩϪ 10.1 104.7 ϩϪ 22.9 111.4 ϩϪ 24.3 25.5 ϩϪ 6.2 84.4 ϩϪ 10.6 Ͻ 0.001 Caspase-3 : PCNA ratio 1.24 ϩϪ 0.07 0.93 ϩϪ 0.11 1.69 ϩϪ 0.54 2.73 ϩϪ 0.57 0.93 ϩϪ 0.27 0.71 ϩϪ 0.09 Ͻ 0.001 MPA, medroxyprogesterone acetate; NETA, norethisterone acetate Climacteric 519 Breast proliferation and apoptosis Pompei et al. In the case of the caspase-3 : PCNA ratio, multiple com- compared to almost all the other groups, except EB.
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