Repositório Institucional - Unifesp :: Navegando por Palavras-chave "tamoxifen"

Navegando por Palavras-chave "tamoxifen"

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Apoptotic index in breast carcinoma cells following tamoxifen treatment
(Elsevier B.V., 2006-10-01) Millen, Eduardo Campos [UNIFESP]; Silva, B. B. da; Gebrim, Luiz Henrique [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Fed Univ Piaui
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Differential gene expression assessed by cDNA microarray analysis in breast cancer tissue under tamoxifen treatment
(I R O G Canada, Inc, 2005-01-01) Wolgien, Maria Del Carmen Garcia Molina [UNIFESP]; Silva, Ismael Dale Cotrim Guerreiro da [UNIFESP]; Villanova, Fabiola Elizabeth [UNIFESP]; Otsuka, Audrey Yumi [UNIFESP]; Borra, Ricardo Carneiro [UNIFESP]; Reis, LFL; Carvalho, A. E.; Baracat, Edmund Chada [UNIFESP]; Gebrim, Luiz Henrique [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Ludwig Inst Canc Res
Our purpose was to identify tamoxifen (TAM) responsive genes after 30 days of TAM treatment in tumor tissues obtained from women with breast cancer using microarray expression analysis. In our study, we identified 12 candidates to be considered as tamoxifen-modulated genes. Among them, we selected two candidates the TEGT BI-1 (testis enhanced gene transcript Bax Inhibitor-1) and the CD63 gene in order to further confirm their differential expression under tamoxifen effects. We observed that both were down-regulated in tumor tissues of patients during TAM treatment. TEGT is able to inhibit the expression of Bax, which is known to promote apoptosis. On the other hand, CD63 encodes a cell membrane protein and it seems to be involved in mechanisms of platelet activation. cell adhesion and cell motility. We therefore hypothesize that TAM would be able to modulate tumor growth by down-regulating genes involved in mechanisms such as cell cycle control, tumor invasion and metastasis.
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Early nuclear alterations and immunohistochemical expression of Ki-67, Erb-B2, vascular endothelial growth factor (VEGF), transforming growth factor (TGF-BETA 1) and integrine-linked kinase (ILK) two days after tamoxifen in breast carcinoma
(Veda, Slovak Academy Sciences, 2004-01-01) Morena, Ana Maria Lira [UNIFESP]; Oshima, Celina Tizuko Fujiyama [UNIFESP]; Gebrim, Luiz Henrique [UNIFESP]; Egami, Mizue Imoto [UNIFESP]; Silva, Maria Regina Regis da [UNIFESP]; Segreto, Roberto Araujo [UNIFESP]; Giannotti Filho, Osvaldo [UNIFESP]; Teixeira, Vicente de Paulo Castro [UNIFESP]; Segreto, Helena Regina Comodo [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Oncoctr Fdn Sao Paulo
The purpose of the present study was to evaluate breast carcinoma samples before and two days after treatment with tamoxifen in order to analyse early histopathological alterations - particularly nuclear alterations - as well as immunohistochemical expression of Ki-67, Erb-B2, VEGF, TGf-beta 1 and ILK proteins. Twenty one cases of invasive ductal and lobular breast carcinoma were studied. Patients were submitted to biopsy of the lesion and, after confirmation of the diagnosis, they received 20 mg of tamoxifen a day, beginning two days before surgery. The samples obtained during biopsy and after surgery were stained with HE for histopathological diagnosis. Estrogen receptor was positive in IS cases and negative in 3. The immunohistochemical method was applied for the detection of Ki-67, Erb-B2, protein, vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-beta 1) and integrin linked kinase (ILK).Two days after tamoxifen treatment, the following results were observed: 1) decrease in the cell volume, chomatine condensation, nucleoli less evident and clearly defined nuclear limits; 2) significant reduction in the expression of Erb-B2 protein and significant increase in the expression of TGF-beta 1 protein; 3) expression of others proteins (Ki-67, VEGF and ILK) was not altered during the indicated time frame.Our results suggest that analyzing nuclear alterations and expression of Erb-B2 and TGF-beta 1 proteins would be useful to assess the initial response to tamoxifen.
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Effect of a half dose of tamoxifen on proliferative activity in normal breast tissue
(Elsevier B.V., 1999-10-01) Bernardes, JRM; Nonogaki, S.; Seixas, M. T.; Lima, G. R. de; Baracat, E. C.; Gebrim, L. H.; Universidade Federal de São Paulo (UNIFESP)
Objectives: To investigate the proliferative activity of the mammary gland epithelium and plasma levels of progesterone, estradiol, prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG) in premenopausal women treated with 10 and 20 mg of tamoxifen (TAM) for 22 days. Patients and methods: A randomized double-blind study was performed with 43 premenopausal women with a diagnosis of fibroadenoma of the breast. the patients were divided into three groups: A (n = 15, placebo); B (n = 15, TAM 10 mg/day) and C (n = 13, TAM 20 mg/day). They started taking an oral dose of TAM or placebo on the very first day of the menstrual cycle. Lumpectomy was performed on the 22nd day of therapy. Normal breast tissue samples were collected during surgery, immediately immersed in 10% buffered formalin, processed for routine histology and immunohistochemistry for proliferating cell nuclear antigen (PCNA) detection. Two peripheral blood samples were collected, both on the 22nd day of the menstrual cycle, in order to evaluate the hormone levels. PCNA expressing epithelial cells were quantified by using a digital program Kontron Image System KS-300 in 1000 cells (400 x). Results: the percentage of cells expressing PCNA was significantly higher in the group receiving placebo (group A, 50.3%) when compared to groups receiving TAM 10 or 20 mg/day (group B, 24.1%; and group C, 23.2%, respectively) (P < 0.001). Differences between groups B and C were not significant. Levels of progesterone, estradiol and SHBG were significantly higher in B and C groups compared to group A. Increasing concentrations of FSH (P < 0.0045) and lower levels of prolactin (P < 0.0055) were only found in the group receiving 20 mg/day of TAM (group C). Conclusions: A 22-day TAM therapy, either with 10 or 20 mg/day, significantly reduced the PCNA expression and therefore the proliferative activity of the normal human breast tissue. Increasing levels of estradiol, progesterone and SHBG were associated with TAM therapy at 10 or 20 mg/day. However, a significant change of the level of FSH and prolactin was reached only with a 20-mg/day dose. (C) 1999 International Federation of Gynecology and Obstetrics.
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The effect of tamoxifen on the proliferative activity of fibroadenomas
(Elsevier B.V., 2002-05-01) Bernardes, JRM; Seixas, M. T.; Gebrim, L. H.; Universidade Federal de São Paulo (UNIFESP)
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Effects of low dose tamoxifen on normal breast tissue from premenopausal women
(Elsevier B.V., 2003-05-01) Lima, G. R. de; Facina, G.; Shida, J. Y.; Chein, MBC; Tanaka, P.; Dardes, Rita de Cássia de Maio [UNIFESP]; Jordan, V. C.; Gebrim, L. H.; Universidade Federal de São Paulo (UNIFESP); Northwestern Univ
The aim of this study was to determine the effects of low doses of tamoxifen (5 and 10 mg/day) for 50 days compared with the standard dose (20 mg/day) on breast biomarkers measured in normal breast tissue from premenopausal patients. A randomised double-blind study was performed using tissue from 56 premenopausal women with a diagnosis of fibroadenoma of the breast. Excisional biopsy was performed on the 50th day of therapy. Normal breast tissue samples were collected during surgery. the patients were divided in groups: A (placebo, n = 11); group B (5 mg, n = 16), group C (10 mg, n = 14) and group D (20 mg, n = 15). in this cross-sectional study, differences in the expression of Oestrogen Receptor alpha (ERalpha), Progesterone Receptor (PR), Ki-67, apoptotic bodies and mitotic index between the different groups after treatment can be seen on the normal breast tissue. We believe that a lower dose of tamoxifen could reduce the side-effects associated with treatment without affecting its chemopreventive activity in the breast. (C) 2003 Elsevier B.V. All rights reserved.
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Effects of tamoxifen on the breast in the luteal phase of the menstrual cycle
(Elsevier B.V., 1998-07-01) Uehara, J.; Nazario, ACP; Lima, G. R. de; Simoes, M. J.; Juliano, Y.; Gebrim, L. H.; Universidade Federal de São Paulo (UNIFESP)
Objectives: the effect of tamoxifen on cyclic mastalgia and on chemoprophylaxis against breast cancer is little known, mainly due to the difficulties in studying the normal human gland. We proposed to evaluate the mitotic index and the nuclear volume of the lobule of women medicated with tamoxifen only during the luteal phase of the menstrual cycle in order to observe the effect of tamoxifen on the normal human mammary gland. Methods: Twenty-four premenopausal women with fibroadenoma diagnosed via biopsy were studied. the phase of the cycle was determined by the date of menstruation and serum progesterone level in the luteal phase (greater than or equal to 3 ng/ml). the patients admitted to the study and were given written informed consent to participate in the investigation, which was previously approved of by the hospital Ethics Committee. Patients were divided at random into two groups: Group I consisted of 12 untreated women (control) and Group II consisted of 12 patients treated with 20 mg/day tamoxifen for 10 consecutive days beginning on the 13th day of the menstrual cycle. in both groups, the patients were submitted to biopsies of the nodule and of a 1-cm(3) fragment of adjacent mammary parenchyma between the 23rd and 26th day of the cycle. the mitotic index (number of mitoses/1000 nuclei counted) and mean nuclear volume (mean of 10 nuclear volumes for each case) were measured. Results: No mitosis was observed in Group II. There was a reduction in the mean nuclear volume in Group II (Mann-Whitney test). Conclusions: Tamoxifen, when administered only during the luteal phase of the menstrual cycle, significantly reduces the nuclear volume and mitotic activity of the epithelium. This data demonstrates an antagonistic action of tamoxifen on estrogen even when administered for short periods of time. (C) 1998 International Federation of Gynecology and Obstetrics.
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Effects of tamoxifen therapy on the expression of p27 protein in the endometrium of women with primary breast cancer
(Professor D A Spandidos, 2003-12-01) Siufi, Adalberto Abraao [UNIFESP]; Silva, Ismael Dale Cotrim Guerreiro da [UNIFESP]; Dardes, Rita de Cássia de Maio [UNIFESP]; Takita, Luiz Carlos [UNIFESP]; Lima, Geraldo Rodrigues de [UNIFESP]; Goncalves, Wagner Jose [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
The cyclin-dependent kinase inhibitor, p27, has been shown to mediate cell growth arrest thereby significantly reducing the percentage of proliferating cells. It seems that p27 expression is essential for the control of normal endometrial proliferation, and reduced or absent p27 expression may be an important step in endometrial carcinogenesis. Our aim was to demonstrate the effects of tamoxifen therapy on the expression of p27 protein in the endometrium of postmenopausal breast cancer patients. Fifty-three pre- and post-tamoxifen treatment endometrium samples were examined immunohistochemically using p27 antibody. Tamoxifen therapy (20 mg/day) for 60 days increased the expression of p27 protein in the endometrium of postmenopausal breast cancer patients. We conclude that tamoxifen therapy does not seem to be directly involved in the carcinogenesis of endometrial carcinoma since the expression of p27 is not decreased.
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Estrogen and selective estrogen receptor modulator regulation of insulin-like growth factor binding protein 5 in the rat uterus
(Parthenon Publishing Group, 2002-08-01) Andrade, P. M.; Silva, IDCG; Borra, R. C.; Lima, G. R.; Baracat, E. C.; Universidade Federal de São Paulo (UNIFESP)
Insulin-like growth factor (IGF) binding protein 5 (IGFPB-5) is abundant in the uterus and is implicated in the sex steroid-induced growth of this tissue. the purpose of this study was to investigate the potential for modulation of the action of IGFPB-5 at the uterus level in the rat by estrogen alid selective estrogen receptor modulators (SERMs).One hundred and twenty adult rats, 2-3 months of age, were included. Among them 100 animals were ovariectomized 4 days prior to the use of drugs for 48 days. Rats were divided into six groups: non-ovariectomized (group 1); ovariectomized (group 2); and those receiving conjugated equine estrogens, 50 mug/day (group 3), tamoxifen 250 mug/day (group 4), raloxifene 3 mg/kg (group 5) and toremifene 2.5 mg/kg (group 6). Total RNA was isolated from the uterus and IGFP-5 mRNA levels were assessed by the semiquantitative reverie transcription polymerase chain reaction (RT-PCR).Our results demonstrate that conjugated equine estrogens were able to up-regulate mRNA levels of the IGFBP-5 gene, while oophorectomy alone as well as associated with hormone therapy such as tamoxifen, raloxifene and toremifene resulted in down-regulation of uterine IGFBP-5 gene expression.The up-regulation of IGFBP-5 expression induced by estrogens sugests that, in vivo, the uterotrophic effects of estrogen replacement therapy are mediated, at least in part, by the IGF pathways. On the other hand, the use of SERMs (tamoxifen, raloxifene and toremifene) was associated with severe down-regulation of this gene at the transcription level.
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Estrogen, progestogen and tamoxifen increase synaptic density of the hippocampus of ovariectomized rats
(Elsevier B.V., 2000-09-22) Silva, I; Mello, LEAM; Freymuller, E.; Haidar, Mauro Abi [UNIFESP]; Baracat, E. C.; Universidade Federal de São Paulo (UNIFESP)
The effects of gonadal steroids or tamoxifen over the synaptic density of the CA1 region of the hippocampus was investigated in ovariectomized (OVX) rats. Chronic oral administration of conjugated equine estrogen, conjugated equine medroxyprogesterone, a combination of both or tamoxifen was performed in ovariectomized (OVX) rats over a period of 60 days. Synaptic density of the stratum radiatum of the CA1 region was evaluated by means of electron microscopy. Significant increases in the range of 34-49% were found for treated animals as compared to OVX controls not subject to hormonal replacement. Our results confirm previously reported effects of estradiol over synaptic density in this region and reports for the first time an effect of medroxyprogesterone (alone or in combination with estrogen) and tamoxifen. Our findings support the notion that hormonal replacement therapy and tamoxifen might have beneficial effects for cognitive function. (C) 2000 Published by Elsevier Science Ireland Ltd.
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Estrogenic activity of tamoxifen on normal mammary parenchyma in the luteal phase of the menstrual cycle
(Elsevier B.V., 1997-01-01) Facina, G.; deLima, G. R.; Simoes, M. J.; Novo, N. F.; Gebrim, L. H.; Universidade Federal de São Paulo (UNIFESP)
Objectives: Tamoxifen, an anti-estrogenic drug used in the adjuvant treatment of breast cancer, deserves more investigation for the determination of its efficacy as a prophylactic agent against breast cancer in high risk women. Thus, the action of tamoxifen on the human mammary gland was studied by measuring the number of lysosomes in normal mammary epithelium during the administration of tamoxifen. Methods: Tamoxifen was administered only during the luteal phase of the menstrual cycle to avoid interference with corpus luteum formation. A fragment of breast tissue adjacent to a fibroadenoma was obtained during surgery from 35 premenopausal women aged 15 to 37 years who had been eumenorrheic for at least 6 months; 18 of these patients were treated with tamoxifen and 17 were used as controls. Lysosome counts were performed under the light microscope on slides submitted to the acid phosphatase cytochemical technique and the data were analyzed statistically by the Mann-Whitney test. Results: the fragments from the group treated with tamoxifen showed a significant decrease in lysosome numbers. Conclusions. Tamoxifen administered after ovulation significantly decreases the number of lysosomes in the cells of normal mammary epithelium, demonstrating the antiestrogenic effect of the drug on this target tissue. (C) 1997 International Federation of Gynecology and Obstetrics.
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Hysteroscopic evaluation of the endometrium of post-menopausal patients with breast cancer before and after tamoxifen use
(Elsevier B.V., 1999-09-01) Goncalves, MAG; Goncalves, Wagner Jose [UNIFESP]; Matias, M. M.; Nazario, ACP; Lima, G. R. de; Baracat, E. C.; Pontificia Univ Catolica Rio Grande do Sul; Universidade Federal de São Paulo (UNIFESP); Porto Alegre Gen Hosp
Objective: To evaluate by hysteroscopy and histopathology the influence of tamoxifen in the endometrium df post-menopausal women with previous breast cancer. Method: Out of 46 patients studied, 20 of them had been using tamoxifen for an average length of 12 months, and are still being followed-up. Hysteroscopy with endometrial biopsy was performed before and after the use of the drug. Results: the prevalence of endometrial activity before and after this hormoniotherapy was the same, i.e. 10.0%, showing a non-significant variation. Conclusion: the hormoniotherapy with tamoxifen has not increased the endometrial proliferactive activity of postmenopausal patients with breast cancer. the most common hysteroscopical finding was numerous vesicles disseminated throughout the uterine cavity probably due to atrophy of the endometrium, (C) 1999 International Federation of Gynecology and Obstetrics.
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Morphological action of tamoxifen in the endometrium of persistent estrous rats
(Munksgaard Int Publ Ltd, 1996-09-01) Patriarca, M. T.; Simoes, R. D.; Smaniotto, S.; DeTeves, D. C.; Simoes, M. J.; EvencioNeto, J.; DeFreitas, V; DeLima, G. R.; Universidade Federal de São Paulo (UNIFESP)
Background. the aim of this study was to evaluate the action of tamoxifen on the endometrium in stales of chronic anovulation.Methods. Thirty-eight rats inducted to persistent estrous (testosterone propionate) confirmed by hormonal colpocytology were divided into a control and an experimental group; the latter received tamoxifen and had fragments of the uterine horns processed for morphological and morphometrical analysis. Data were analysed statistically by the Mann-Whitney and Student's t tests.Results. Our findings revealed minor uterine weight, epithelial thickness; number of endometrial glands and low eosinophil counts in the group that received tamoxifen. These results were statistically significant. We often observed areas of metaplasic stratified squamous epithelium between cylindrical epithelial cells in both groups.Conclusions. Our results indicate that antiestrogenic effect of tamoxifen was only partial in persistent estrous, since there was no blocking against the squamous metaplasia of the endometrium.
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Multifocal electroretinography, color discrimination and ocular toxicity in tamoxifen use
(Taylor & Francis Inc, 2007-04-01) Salomão, Solange Rios [UNIFESP]; Watanabe, Sung Eun Song [UNIFESP]; Berezovsky, Adriana [UNIFESP]; Motono, Marcia; Universidade Federal de São Paulo (UNIFESP); Antonio Prudente Fdn
Purpose: To study prospectively retinal function, color discrimination, and ocular toxicity in women treated with standard-dosage tamoxifen for breast cancer. Methods: Thirty visually asymptomatic patients with at least 2 years of continuous tamoxifen therapy underwent multifocal electroretinography (ERG), color discrimination testing, and ophthalmic examination. the results were compared with 17 patients who were not taking tamoxifen after breast cancer surgery and to an additional age-matched group of 21 healthy women. Results: Multifocal electroretinogram amplitudes and latencies were comparable among the three studied groups, and individual recordings were within age norms from our own lab. in the treated group, mild diffuse color vision loss was found in two patients with normal fundi. Three other patients had ocular toxic effects, with two cases of refractile retinal crystals and one case of keratopathy. Conclusions: the aspects of central retinal function that are assessed by multifocal ERG were not affected even after at least 2 years of tamoxifen use, suggesting that the multifocal ERG is not sufficiently sensitive to detect tamoxifen-associated change that might occur. Some degree of color vision loss and ocular toxic effects were found in a few cases of this cohort suggesting that women using tamoxifen should receive an eye exam at least as often as recommended for middle-aged people.
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A pilot study of the effects of short-term tamoxifen therapy on Ki-67 labelling index in women with primary breast cancer
(Professor D A Spandidos, 2000-01-01) Dardes, Rita de Cássia de Maio [UNIFESP]; Horiguchi, J. [UNIFESP]; Jordan, V. C. [UNIFESP]; Northwestern Univ; Universidade Federal de São Paulo (UNIFESP); Gunma Univ
In this study we demonstrate the change in estrogen receptor (ER) level and cell proliferation in human breast cancer after a short-term tamoxifen therapy. Ten pre and post-treatment breast tumor samples were examined immunohistochemically using ER and Ki-67 antibodies. Before tamoxifen treatment, six (60%) of ten patients were positive for ER. Tamoxifen increased the ER level in one patient and decreased the level in 4 patients. There was no significant change in ER level by tamoxifen therapy. On the other hand, Ki-67 labelling index (LI) significantly decreased after tamoxifen treatment. When Ki-67 LI was analyzed according to ER level, there was no difference between pre- and post-tamoxifen treatment in ER-negative patients, however, a significant decrease of Ki-67 LI by tamoxifen treatment was seen in ER-positive patients. Patients who showed down-regulation of ER expression tended to show a decrease of Ki-67 LI after tamoxifen therapy. In conclusion, short-term tamoxifen therapy decreased the proliferation of breast cancer, in ER-positive breast tumor samples.
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Quantification of angiogenesis induced in rabbit cornea by breast carcinoma of women treated with tamoxifen
(Wiley-Blackwell, 2005-05-01) Da Silva, B. B.; Da Silva, R. G.; Borges, U. S.; Filho, MAGD; Pimentel, ICC; Gebrim, L. H.; Simoes, M. D.; Baracat, E. C.; Fed Univ Piaui; Universidade Federal de São Paulo (UNIFESP)
Background: the aim of this study was to evaluate the effect of tamoxifen on angiogenesis induced in rabbit cornea by breast curcinoma from post-menopausal women.Methods: Thirteen post-menopausal women with operable, estrogen receptor-positive breast carcinomas, treated with 20 mg of tamoxifen daily for 30 days prior to undergoing definitive surgery, participated in this study. Twenty-six virgin female New Zealand white rabbits, 3-4 months old, weighing approximately 2.5 kg each, were divided into two groups of 13 animals and received corneal implants of tumor either pre- or post-tamoxifen treatment. After 10 days, tie animals were sacrificed, the region of the cornea between the tumor implant and the limbus was removed and quantification of angiogenesis was carried out by eualuating the entire hematoxylineosin stained slide, using a 10x objective lens (100x magnification). Student t-test was used in the statistical analysis of the data and statistical significance was established at P < 0.05.Results: Mean microvessel count was 106.8 +/- 5.9 pre-tamoxifen treatment and 54 +/- 5.6 post-treatment. According to Student t-test, there was a significant reduction in mean microvessel density following treatment with tamoxifen (P < 0.001).Conclusions: Rabbit cornea proved to be an interesing experimental model for the quantification of angiogenesis. Tamoxifen, when administered for 30 days to postmenopausal women with breast cancer, significantly inhibited angiogenesis induced by tumor fragments in rabbit cornea. (C) 2005 Wiley-Liss, Inc.
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Raloxifene-stimulated experimental breast cancer with the paradoxical actions of estrogen to promote or prevent tumor growth: A unifying concept in anti-hormone resistance
(Spandidos Publ Ltd, 2010-08-01) Balaburski, Gregor M.; Dardes, Rita de Cássia de Maio [UNIFESP]; Johnson, Michael; Haddad, Bassem; Zhu, Fang; Ross, Eric A.; Sengupta, Surojeet; Klein-Szanto, Andres; Liu, Hong; Lee, Eun Sook; Kim, Helen; Jordan, V. Craig; Georgetown Univ; Fox Chase Canc Ctr; Universidade Federal de São Paulo (UNIFESP); Northwestern Univ
We have previously demonstrated that prolonged treatments with raloxifene (RAL) in vitro will result in phase II RAL resistance and RAL-induced tumor growth. Clinical interest prompted us to re-examine RAL resistance in vivo, particularly the effects of long-term treatments (a decade or more) on the evolution of RAL resistance. in this study, we have addressed the question of this being a reproducible phenomenon in wild-type estrogen receptor (ER)-positive human breast cell line MCF-7. MCF-7 cells cultured under estrogen-deprived conditions in the presence of 1 mu M RAL for more than a year develop RAL, resistance resulting in an independent cell line, MCF7-RAL. the MCF7-RAL cells grow in response to both estradiol E, and RAL. Fulvestrant (FUL) blocks RAL and E(2)-mediated growth. Transplantation of MCF7-RAL cells into athymic ovariectomized mice and treatment with physiologic doses of E(2) causes early E(2)-stimulated tumor growth. in contrast, continuous treatment of implanted animals with daily oral RAL (1.5 mg daily) causes growth of small tumors within 15 weeks. Continuous re-transplantation of the tumors growing in RAL-treated mice indicated that RAL, stimulated tumor growth. Tumors in the untreated mice did not grow. Bi-transplantation of MCF7-E(2) and MCF7-RAL tumors into the opposing mammary fat pads of the same ovariectomized animal demonstrated that MCF7-E(2) grew with E(2) stimulation and not with RAL. Conversely. MCF7-RAL tumors grew with RAL and not E(2) a characteristic of phase II resistance. Established phase II resistance of MCF7-RAL tumors was confirmed following up to 7 years of serial transplantation in RAL-treated athymic mice. the ER alpha was retained in these tumors. the cyclical nature of RAL resistance was confirmed and extended during a 2-year evolution of the resistant phases of the MCF7-RAL tumors. the MCF7-RAL tumors that initially were inhibited by E(2) grew in the presence of E(2) and subsequently grew with either RAL or E(2). RAL remained the major grow stimulus and RAL enhanced E(2)-stimulated growth. Subsequent transplantation of E(2) stimulated tumors and evaluations of the actions of RAL, demonstrated robust E(2)-stimulated growth that was blocked by RAL. These are the characteristics of the anti-estrogenic actions of RAL on E(2)-stimulated breast cancer growth with a minor component of phase I RAL resistance. Continuous transplantation of the phase I RAL-stimulated tumors for >8 months causes reversion to phase II resistance. These data and literature reports of the cyclical nature of anti-androgen/androgen responsiveness of prostate cancer growth, illustrate the generality of the evolution of anti-hormonal resistance in sex steroid-sensitive target tissues.
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Regulation of estrogen target genes and growth by selective estrogen-receptor modulators in endometrial cancer cells
(Elsevier B.V., 2002-06-01) Dardes, Rita de Cássia de Maio [UNIFESP]; Schafer, J. M.; Pearce, S. T.; Osipo, C.; Chen, B.; Jordan, V. C.; Universidade Federal de São Paulo (UNIFESP); Northwestern Univ
Objective. Tamoxifen has mixed agonist/antagonist activities, leading to tissue-specific estrogen-like actions and endometrial cancer. the purpose of this study was to evaluate the effects of antiestrogens on the growth of estrogen receptor (ER)-positive ECC-1 endometrial cancer cells in vitro and in vivo.Methods. We performed growth studies and luciferase assays using ERE-tK and AP-1 reporters. ERalpha protein expression was measured by Western blot after antiestrogen treatments. We investigated the actions of antiestrogens on the transcription of the pS2 gene in situ measured by Northern blot and the actions of antiestrogens on the VEGF protein secreted by ELISA. ERa, ERbeta, EGFR, and HER2/neu mRNAs were determined by RTPCR. Last, ECC-1 tumors were developed by inoculation of cells into ovariectomized athymic mice and treated with estradiol (EA tamoxifen, raloxifene, and a combination.Results. E-2 induced cell proliferation while antiestrogens did not. E2 and raloxifene down regulated ERa protein; in contrast, 4OHT did not. IC1182,780 completely degraded the receptor. ECC-1 cells express ER,6 at insignificant levels. Luciferase assays did not show any induction in ERE- nor AP-1-mediated transcription by antiestrogens. E2 caused a concentration-dependent increase in pS2 mRNA but antiestrogens did not. E, increased VEGF expression in a dose-dependent manner and antiestrogens blocked E2 action. E. down regulated HER2/neu while 40HT and raloxifene did not change HER2/neu levels compared to control. in addition, EGFR mRNA was down regulated by E, but raloxifene did not change it. Tamoxifen and raloxifene did not promote tumor growth in vivo. However, raloxifene (1.5 mg daily) only partially blocked E-stimulated growth.Conclusions. Tamoxifen and raloxifene are anti proliferative agents and antiestrogens in ECC-1 endometrial cells in vitro and in vivo. the observation that selective estrogen-receptor modulators do not down regulate EGFR and HER2/neu mRNA may provide a potential role for these oncogenes in the development of raloxifene- or tamoxifen-stimulated endometrial cancer. the ECC-1 cell line could provide important new clues about the evolution of drug resistance to tamoxifen and raloxifene. (C) 2002 Elsevier Science (USA).

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