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Tamoxifen Stimulates Human Papillomavirus Type 16 Gene Expression and Cell Proliferation in a Cervical Cancer Cell Line 1

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Tamoxifen Stimulates Human Papillomavirus Type 16 Gene Expression and Cell Proliferation in a Cervical Cancer Cell Line 1 [CANCER RESEARCH 52, 6848-6852, December 15, 1992] Tamoxifen Stimulates Human Papillomavirus Type 16 Gene Expression and Cell Proliferation in a Cervical Cancer Cell Line 1 Jin-Yun Hwang, 2 Bi-Yu Lin, 3 Fen-Mei Tang, 3 and Winston C. Y. Yu 3 Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan, Republic of China ABSTRACT genes such as PR and collagenase in cultured MCF-7 cells (31, 32). These side effects of tamoxifen are important to take The widely adopted use of tamoxifen as a chemotherapeutic agent is into account when considering the long-term clinical usage of primarily based on its inhibition of cancer cell growth. However, we tamoxifen for adjuvant therapy and as preventive medicine. The report that tamoxifen at low concentrations (10 -9 and 10 -1~ M) causes stimulation of cell proliferation in a cervical cancer cell line, SFR. The purpose of this study was to examine the effect of tamoxifen on facts that SFR cells do not contain estrogen receptors and are estrogen cell growth using a cervical cancer cell line (SFR) as a model nonresponsive imply the existence of an antiestrogen-specific binding and to elucidate the possible mode of action of tamoxifen protein and suggest that the effect of tamoxifen is possibly mediated through a specific gene, HPV-16, which is crucial in regulating through a pathway other than estrogen receptors. Tamoxifen at low cervical cancer cell growth. concentrations stimulated human papiilomavirus type 16 (HPV-16) HPV-I 6 is the most prevalent virus associated with the gen- gene transcription and E7 protein production. Levels of HPV-16 mRNA esis of cervical malignant lesions (33-35). Open reading frames and E7 protein reached a peak at approximately 2-4 h after tamoxifen E6 and E7 are present and integrated in the majority of cervical treatment, persisted for several hours, and subsequently decreased to cancer biopsy specimens (36). Laboratory studies have also their prestimulation levels by about 24 h after treatment. Our results demonstrated that E6 and E7 genes can transform or immor- indicate for the first time that tamoxifen stimulates cell proliferation of cervical cancer cells, and we suggest that the enhanced HPV-16 mRNA talize human keratinocytes and embryonic fibroblasts (37, 38). and E7 protein levels are probably responsible. Specific inhibition of E6 and E7 gene expression in cervical cancer cells by antisense RNA leads to significantly reduced cell INTRODUCTION growth (39). The effects of E6 and E7 on cell proliferation are further supported by studies using dexamethasone-treated cer- The inhibitory effect of tamoxifen on estrogen action has vical cancer cells, whose growth rate is positively correlated been studied quite extensively (1-4). Tamoxifen retards estro- with the expression of papillomavirus E6 and E7 genes (40). gen-stimulated tumor growth and has been used clinically not Taken together, these data suggest that gene expression of E6 only as a chemotherapeutic agent (2-4) but also for preventive and E7 is a limiting factor in both the regulation of cell growth treatment of breast cancer in recent years (5). It has been pro- and maintenance of the malignant state. Various factors have posed that the mechanism of action of tamoxifen is mediated been reported to play important roles in regulating viral gene through ER 4, as suggested by the results of competitive binding expression in host cells. Factors identified so far include gluco- studies (1, 6). However, many breast tumors are ER negative, corticoid hormones and progesterone (41, 42), gene products of and 10-13% may exhibit a positive response to antiestrogen open reading frame E2 (43), and a keratinocyte-specific enhanc- therapy (7-9). Laboratory studies have revealed that the active ing factor (38). In this report, we provide evidence that tamox- metabolite of tamoxifen, OHT, strongly inhibits an ER-nega- ifen is another factor that can affect HPV-16 viral gene expres- tive and a PR-negative breast cancer cell line (10, 11). It is sion and that an enhanced E7 protein level may be related to the apparent that the sensitivity of cells to the growth inhibitory long-suspected stimulatory effect of tamoxifen on cell growth. effect of tamoxifen does not always correlate with ER status (11-15). A saturable high-affinity antiestrogen-binding protein MATERIALS AND METHODS has been demonstrated in a wide variety of tissues and cell lines (16-20). Thus, antiestrogen-binding sites have been suggested Chemicals. [N-methyl-3H]-tamoxifen (82.6 Ci/mmol) was pur- as possible alternative mediators for tamoxifen function in chased from NEN (Boston, MA) and stored, protected from light, in some ERonegative cells (10, 18, 20, 21). The stimulatory effect ethanol at -20~ [35S]Methionine was purchased from Amersham of tamoxifen on cell growth is an even more complicated issue, Corp. (Buckinghamshire, England). Radioinert tamoxifen, 17~-estra- however. Numerous studies have revealed a partial estrogenic diol, progesterone, and triamcinolone acetonide were obtained from Sigma Chemical Co. (St. Louis, MO), prepared as l0 mM stock solu- effect exerted by tamoxifen and its active metabolite OHT in tions in ethanol, and stored at 4~ The GAPDH DNA-containing various model systems, including breast cancer cells both in plasmid was a gift from Dr. Selina Chen-Kiang (Mt. Sinai Medical culture (22-24) and in nude mice (25, 26), endometrial adeno- School, New York). Anti-HPV-16 E7 antibody was purchased from carcinoma cells in athymic mice (27), and uterine tissue in Triton Diagnostics (Alameda, CA). Epidermal growth factor was ovariectomized rats and mice (28-30). Moreover, tamoxifen purchased from Collaborative Research Inc. (Bedford, MS). Sigma and OHT can stimulate the expression of estrogen-regulated was also the source of insulin, transferrin, cholera toxin, kanamycin monosulfate, hydrocortisone, NP-40, sodium orthovanadate, protein Received 6/12/92; accepted 10/6/92. A-Sepharose, 2-mercaptoethanol, and aprotinin. Penicillin and strep- The costs of publication of this article were defrayed in part by the payment of tomycin were obtained from Gibco BRL (Gaithersburg, MD). The page charges. This article must therefore be hereby marked advertisementin accord- oligo(dT)-ceUulose, phenylmethylsulfonyl fluoride, and leupeptin were ance with 18 U.S.C. Section 1734 solely to indicate this fact. I Supported in part by National Science Council Grant 81-0412-B-001-04 to obtained from Mannheim Boehringer GmbH (Mannheim, Germany). W. C. Y. Y. Sodium fluoride and tetrasodium pyrophosphate were bought from 2 National University Preparatory School for Overseas Chinese Students. Merck (Darmstadt, Germany). 3 To whom requests for reprints should be addressed. Cell Culture. SFR cells, a subline of the cervical carcinoma cell line 4 The abbreviations used are: ER, estrogen receptor; OHT, 4-hydroxytamoxifen; PR, progesterone receptor; HPV-16, human papiliomavirus type 16; NP-40, non- CaSki, were routinely cultured in serum-free media using T-75 flasks or idet P-40; SDS, sodium dodecyl sulfate; poly(A)+, polyadenylated; GAPDH, glyc- 150-cm 2 dishes and kept in a humidified incubator at 370C under a 5% eraldehyde 3-phosphate dehydrogenase. CO2-enriched atmosphere. Serum-free media consisted of F-12 basal 6848 Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1992 American Association for Cancer Research. TAMOXIFEN STIMULATION OF HPV-16 GENE EXPRESSION media supplemented with 5 ~tg/ml insulin, 5 ug/ml transferrin, 362.5 progesterone, 173-estradiol, and triamcinolone acetonide as indicated ng/ml hydrocortisone, 40 ng/ml cholera toxin, 25 ng/ml epidermal in the figure legends. All studies were performed in triplicate. growth factor, 100 units/ml penicillin, 100 ttg/ml streptomycin, and 1.25 #g kanamycin. SFR cells were subcultured by trypsinization every 8 days, with media changed on the fourth and sixth day. The seeding RESULTS density of cells was 6 x 10 6 cells per T-75 flask. Cell growth studies Effect of Tamoxifen on Cell Growth. Various concentrations were conducted in 6-well plates with 7 x 104 cells seeded/well. Cells of tamoxifen were tested for their effects on SFR cell growth were allowed to grow and attach for 24 h before experiments started. Northern Blotting. Total RNA from SFR cells was isolated by the during a 5-day period (Fig. 1). Tamoxifen exhibited a biphasic acid guanidium thiocyanate-phenol-chloroform extraction method action according to dose; it stimulated cell growth at low con- (44). Poly(A)+ RNA was isolated by oligo(dT)-cellulose chromatogra- centrations (10 -9 and 10 -ll M), whereas high concentrations of phy as previously described (45). Poly(A)+ RNA (2.5 ~tg) was analyzed tamoxifen (10 -6 and 10 -7 M) showed inhibitory effects. The by agarose gel (1%) electrophoresis and transferred to Hybond-C extra increased cell growth could only be observed toward the later cellulose membrane, which was then hybridized with a 32p-labeled stage of the growth curve after 4 to 5 days of treatment, sug- HPV-16 genomic probe. Hybridizations were performed at 65~ in gesting a cumulative effect of tamoxifen. We have observe a hybridization buffer (0.5 M sodium phosphate, pH 7.4-7% SDS-I% similar stimulatory effect of tamoxifen at a concentration of nonfat milk-2.5 mM EDTA-100 ttg/ml single-strand salmon sperm 10 -9 M in at least 3 separate experiments (data not shown). DNA). At the end of hybridization, blots were washed sequentially in Effect of Tamoxifen on HPV-16 Gene Expression. The effect buffer A (0.2% SDS-2x standard sodium citrate containing 0.3 M NaCl- of tamoxifen on HPV-16 gene expression in SFR cells in their 0.03 M sodium citrate, pH 7.0) twice at 42~ for 10 min, twice at 50"C third day of growth was first revealed by a Northern blot using for 10 min, and then in buffer B (0.04% SDS-0.4x standard sodium poly(A) + RNA as shown in the time-course study (Fig.
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