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Role of Matrix Metalloproteinase 9 in Pituitary Tumor Behavior

Departments of Endocrinology (H.E.T., J.A.H.W.) and Neuropathology (Zs.N., M.M.E.), Radcliffe Infirmary, Department of Pharmacology (Zs.N.), University of Oxford, and Molecular Angiogenesis Group (A.L.H.), Imperial Cancer Research Fund, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX2 6HE, United Kingdom

Address correspondence and requests for reprints to: Prof. J. A. H. Wass, Department of Endocrinology, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, United Kingdom.

	Abstract

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The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that are able to degrade the extracellular matrix and allow angiogenesis and tumor invasion. The vast majority of pituitary tumors are benign and do not metastasize to distant sites, although they may invade locally. The aim of this study was to determine whether expression of the collagenase MMP-9 may play a role in allowing angiogenesis and invasion by different pituitary tumor types. Tumor expression of MMP-9 was investigated using a monoclonal antibody on a series of well-characterized paraffin-embedded sections of pituitary tumors.

Invasive macroprolactinomas (n = 11) were significantly more likely to express MMP-9 than noninvasive macroprolactinomas (n = 8) (P = 0.003). Invasive macroprolactinomas showed higher-density MMP-9 staining than noninvasive tumors (P < 0.05). MMP-9 expression did not differ between noninvasive tumors and normal pituitary gland, or between different sized prolactinomas. MMP-9 expression was related to aggressive tumor behavior. It was higher in invasive macroprolactinomas (P = 0.003) when compared with noninvasive macroprolactinomas or the normal anterior pituitary gland. In addition, although there was no difference in whether MMP-9 was present or not when nonfunctioning adenomas that recurred were compared with those that did not, samples of recurrent tumor at the second presentation were more likely to express MMP-9 (P = 0.01). Pituitary carcinomas were significantly more likely to be MMP-9 positive compared with normal anterior pituitary gland (P = 0.05), but there was no difference from invasive adenomas. Angiogenesis assessed by vascular density was related to MMP-9 expression (P < 0.05).

In summary, we have shown the presence of MMP-9 expression in some invasive and recurrent pituitary adenomas, and in the majority of pituitary carcinoma. The mechanisms whereby MMP-9 expression influences tumor recurrence and invasiveness, and its association with angiogenesis, remains to be elucidated. However, these observations suggest that a future potential therapeutic strategy for some pituitary tumors may be administration of a synthetic MMP-9 inhibitor.

	Introduction

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PITUITARY TUMORS are common incidental findings in approximately 10% of the population, and yet clinically relevant tumors due to either endocrine or mass effects are much less common (1, 2). Despite the fact that the majority of tumors are benign and do not metastasize, a proportion will become locally invasive, leading to bony destruction and infiltration within the cavernous sinus or elsewhere around the pituitary fossa. The surgical treatment of these invasive tumors is often incomplete, and, therefore, therapy to prevent further tumor growth and/or lower excessive hormone secretion is required. The reasons for these differences in tumor behavior are poorly understood, and there are, at present, no reliable mechanisms for predicting tumor behavior.

The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that are able to degrade the extracellular matrix, with each MMP acting on different or overlapping sets of substrate (3, 4). The activity of the MMPs is balanced by the tissue inhibitors of metalloproteinases (5, 6, 7, 8). MMP-2 and MMP-9 are both type IV collagenases, which have been shown to be important in tumor invasion in vitro because they are able to break down basement membrane, in particular, degrading collagen IV (6, 9). Elevated levels of circulating MMP-9 have been demonstrated in patients with breast cancer (10), and MMP-2 and/or MMP-9 release has been associated with tumor invasion and metastasis (11, 12, 13, 14, 15). Some authors have suggested that altered expression of MMP-9 in addition to MMP-11 characterizes epithelial tumors committed to malignant transformation, possibly relating to underlying genetic events that change the tumor phenotype to invasive (16).

The secretion of MMP is an important early process allowing both migration of endothelial cells through the extracellular matrix and angiogenesis to occur (17). In vitro studies have shown that microvascular endothelial cells do not constitutively secrete MMP-9, however, when exposed to an angiogenic stimulus (e.g. tumor necrosis factor ), MMP-9 production is up-regulated (18). Angiogenesis can be inhibited by both endogenous tissue inhibitors of metalloproteinases (19, 20) and administration of synthetic MMP inhibitors (e.g. KB-R7785) (21, 22). In addition to the permissive effects on angiogenesis, MMP-9 has also been shown to have angiostatin-converting enzyme activity, cleaving plasminogen to angiostatin and, thus, potentially enhancing inhibition of angiogenesis (23) and leading to a "balance" of proangiogenic activity and inhibition (24).

Tumor invasion of surrounding tissues is characteristic of more aggressive and often malignant tumor behavior. One previous small study demonstrated that three invasive pituitary adenomas showed high MMP-9 activity in contrast to four noninvasive tumors (25). We have previously shown that microvascular density as a measure of angiogenesis is higher in invasive macroprolactinomas when compared with noninvasive tumors. However, the mechanism whereby pituitary tumors become invasive is poorly understood. The aim of our study was to further investigate the role of MMP-9 expression and the process of pituitary tumor invasion and its relation to angiogenesis.

	Materials and Methods

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Specimen collection

Fifty-five surgically removed pituitary adenomas and nine pituitary carcinomas (three irradiated) were investigated. There were 5 microprolactinomas, 19 macroprolactinomas, and 31 nonfunctioning pituitary adenomas (NFAs). The nonfunctioning tumors had been removed from unirradiated patients and consisted of 12 nonrecurrent tumors, 7 primary tumors that subsequently recurred, and 12 samples of recurrent NFAs. Nonrecurrent tumors had been followed up for a mean of 133 months. Tumor recurrence was detected on the basis of deterioration in visual fields or increase in tumor mass on pituitary imaging (26). Tumor invasiveness was defined on the basis of the modified Hardy criteria (27). Four specimens of normal anterior pituitary gland obtained from surgery for pituitary tumors (3) and autopsy (1) were also studied. The tissue has been fixed in 4% buffered formalin, dehydrated, and embedded in paraffin. Histological examination and immunohistochemistry for anterior pituitary hormones had been performed previously, and, together with the clinical, biological, and radiological data, were used to fully characterize each tumor type. In addition, Ki-67 LI, bcl-2 expression, and microvascular density (as a measure of angiogenesis) had also been previously assessed using ulex europaeus agglutinin I in this cohort of tissue (28).

Immunohistochemistry

Four-micrometer sections were mounted on aptes (3-aminopropyl triethoxy silane; Sigma, St. Louis, MO)-coated slides, dewaxed, and rehydrated. Endogenous peroxidase activity was blocked using 3% hydrogen peroxide. Microwave pretreatment was performed in sodium citrate buffer (pH 6). Nonspecific primary antibody binding was blocked using FCS at a dilution of 1:20. The primary antibody MMP-9 (R&D Systems, Inc., Minneapolis, MN) was applied overnight at 4C at a dilution of 1:50. Negative controls were performed where the primary antibody was replaced by FCS. Positive controls were included with every experiment. After three washes in phosphate buffered saline, biotinylated antimouse secondary antibody (Insight Corp., Bucks., UK) was applied at 1:200 dilution for 30 min at room temperature, followed by washes. The horseradish peroxidase streptavidin complex (DAKO Biotechnology, Wembley, Middlesex, UK) was applied at a 1:400 dilution for 30 min. Color development was with metal-enhanced diaminobenzidine (Pierce Chemical Co., Rockford, IL) applied for 15 min. The slides were lightly counterstained with hematoxylin.

In addition, double immunostaining was performed with primary antibodies to MMP-9 and CD68, to detect macrophages, and MMP-9 and PRL (DAKO), to demonstrate anterior pituitary tumor cells. For each double-immunostaining experiment, MMP-9 immunostaining was followed by the second primary antibody. Nonspecific antibody binding was blocked using FCS as above, and then the primary antibody was applied for 60 min, followed by washes as described above. The secondary antibody was antimouse for CD68 and antirabbit for PRL, and both were applied at 1:200 for 30 min. The APAAP complex (Vector Laboratories, Inc., Burlingame, CA) was then applied for 30 min, followed by washes. Color development was with fast red substrate (Vector Laboratories, Inc.) applied for 20 min. The slides were lightly counterstained with hematoxylin.

Assessment of MMP-9

Each slide was examined by an observer blinded to the diagnosis and reviewed by a second blinded observer. The sections were graded as to whether there was definite positive staining for MMP-9, and, secondly, a semiquantitative grade from 1–4 was attributed to the positive cases according to proportion of positively stained cells (low-density staining, moderate-density staining, dense staining, and very dense staining).

Statistical analysis

The Statgraphics (Manugistics, Rockville, MD) software package was used. ANOVA and ² (with Yates’ correction) tests were used for categorical data analysis. P < 0.05 was considered to represent statistical significance.

	Results

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Prolactinomas

Invasive macroprolactinomas were significantly more likely to express MMP-9 than noninvasive macroprolactinomas (P = 0.003) (Table 1). In addition, invasive tumors showed higher-density MMP-9 staining than noninvasive tumors (P < 0.05) (Fig. 1). There was no difference between noninvasive tumors and normal pituitary gland in terms of MMP-9 positivity (P = 0.7), or between all macroprolactinomas and microprolactinomas (P = 0.3) (Table 1).

View larger version (10K): [in this window] [in a new window]   Figure 1. MMP expression in invasive and noninvasive macroprolactinomas. Noninvasive, Noninvasive macroprolactinoma; invasive, invasive macroprolactinoma. y-axis MMP9G represents MMP-9 semiquantitative grade. Mean values are shown with error bars indicating the SEM.

View larger version (12K): [in this window] [in a new window]   Figure 2. MMP expression and vascular density in prolactinomas. x-axis: MMP9 negative represents absence of MMP-9 staining; positive represents positive MMP-9 staining. y-axis: UEA1M represents mean Chalkley count after immunostaining with ulex. Mean values are shown with error bars indicating the SEM.

There was no difference in whether MMP-9 was present or not when primary tumors that recurred were compared with those that did not (P = 0.16) (Table 1). However, the tumors removed when they recurred (i.e. at the second presentation) were more likely to express MMP-9 (P = 0.01). Paired cases of the first presentation and then the recurrent tumor were available for four patients. These showed either negative MMP-9 expression in the primary case and positive expression in the recurrent cases (two cases) or increased MMP-9 expression in the recurrent tumor compared with the primary presentation (two cases) (Table 2).

Pituitary carcinomas were significantly more likely to be MMP-9 positive compared with normal anterior pituitary gland (P = 0.05) (Table 1). There was no difference between MMP-9 positivity in pituitary carcinomas compared with invasive adenomas.

MMP-9 expression was often localized adjacent to blood vessels. MMP-9 staining was seen both independently from CD68 and also colocalizing with it, suggesting that it is present both in macrophages and other individual cell types (Fig. 3). MMP did not colocalize with PRL in prolactinomas.

View larger version (168K): [in this window] [in a new window]   Figure 3. Section of pituitary tumor immunostained for MMP-9 [brown ()] and immunostained for PYGM for macrophages [red (<)].

	Discussion

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We have shown that MMP-9 is not expressed by tumor cells in invasive tumors, but that it is found in some macrophages. This is in contrast to the data from Kawamoto et al. (25), who described the presence of MMP-9 in tumor cells in invasive adenomas, but did not report the evidence on which this statement was made. It was also expressed in some unidentified nontumorous cells, which appeared morphologically like macrophages but were not labeled with CD68. It is possible that these may be folliculostellate cells that are "activated" and behaving in a phagocytic manner (29). Schecter and Weiner (30) suggested that these cells may play a role in basement membrane breakdown in pituitary tumors and showed the presence of collagenase activity in cells with morphological features of folliculostellate cells. Although MMP-9 is expressed at sites of active tissue remodeling during development, it is expressed mainly by inflammatory cells later (31). In colorectal tumors, for example, MMP-9 has been reported in macrophages only, in contrast to MMP-2, which was found in tumor epithelium, too (32).

Angiogenesis was related to MMP-9 expression in pituitary tumors. Microvascular density was higher in MMP-9-positive tumors. It is not known whether the increased angiogenesis acts as a stimulant to MMP-9 expression to allow further endothelial migration, or whether the stimulus to angiogenesis also leads to increased MMP-9 expression and, therefore, potentiates tumor invasion. The gene for MMP-9 has been localized to chromosome 20 (33), and targeted disruption of the MMP-9 gene in mice leads to reduced angiogenesis, suggesting that MMP-9 may play a role in controlling angiogenesis (34). A relationship between angiogenesis and basement membrane breakdown has been demonstrated in cartilage, where nitric oxide mediates interleukin 1-induced degradation of the extracellular matrix and subsequent release of basic fibroblast growth factor, which may lead to angiogenesis (35). There are several ongoing trials of synthetic inhibitors of MMP-9 in metastatic tumors of epithelial origin, and, if successful, this may play a role in pituitary tumor management (22).

Wild-type p53 has recently been shown to have transactivating activity at the MMP-2 promoter (36). The transcriptional activator ETS-1 has been shown to induce MMP-9 expression and tumor invasiveness (37), and various neuropeptides including somatostatin, bombesin, and calcitonin induce transactivation of tumor cell MMP-9 expression in breast and prostate cancer cell lines (38). cAMP-responsive element binding protein binding activity has also been demonstrated at the type IV collagenase promoter, and it is known that cAMP-response element binding protein is regulated by hypoxia (39) and also interacts with the HIF-1 response element involved in angiogenesis (40) and the promoter of the cyclin D1 gene involved in initiating the cell cycle (41). Thus, several upstream promoters may be activating MMP-9 expression in pituitary tumors.

In conclusion, we have shown that MMP-9 expression is associated with more aggressive tumor behavior in pituitary tumors and that angiogenesis and MMP-9 expression are clearly linked, although the mechanism remains to be elucidated. It is interesting to speculate that the transcriptional activation of the MMP-9 promoter may play a role in linking tumor behavior, invasiveness, and angiogenesis.

	Acknowledgments

 
We are grateful to Prof. Ashley Grossman and Dr. D. Lowe (St. Bartholomew’s Hospital, London, UK) for providing specimens of pituitary carcinoma for our study.

Received November 10, 1999.

Revised April 6, 2000.

Accepted May 14, 2000.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

1. Kovacs K, Ryan N, Horvath E, Singer W, Ezrin C. 1980 Pituitary adenomas in old age. J Gerontol. 35:16–22.[Abstract]
2. Turner HE, Moore NR, Byrne JV, Wass JAH. 1998 Incidentalomas. Endocrine Related Cancer. 5:131–150.[Abstract]
3. Murphy G, Docherty AJP. 1992 The matrix metalloproteinases and their inhibitors. Am J Respir Cell Mol Biol. 7:120–125.
4. Stetler-Stevenson WG, Krutsch HC, Liotta LA. 1989 Tissue inhibitor of metalloproteinase (TIMP-2). A new member of the metalloproteinase inhibitor family. J Biol Chem. 264:17374–17378.[Abstract/Free Full Text]
5. Sellers A, Murphy G, Meikle MC, Reynolds JJ. 1979 Rabbit bone collagenase inhibitor blocks the effects of other neutral metalloproteinases. Biochem Biophys Res Commun. 87:581–587.[CrossRef][Medline]
6. Stetler-Stevenson WG, Liotta LA, Kliener DE. 1993 Extracellular matrix 6: role of matrix metalloproteinases in tumour invasion and metastasis. FASEB J. 7:1434–1441.[Abstract]
7. Uria JA, Ferrando AA, Velasco G, Freije JMP, Lopez-Otin C. 1994 Structure and expression in breast tumours of human TIMP-3, a new member of the metalloproteinase family. Cancer Res. 54:2091–2094.[Abstract/Free Full Text]
8. Ponton A, Coulombe B, Skup D. 1991 Decreased expression of tissue inhibitor of metalloproteinases in metastatic tumour cells leading to increased collagenase activity. Cancer Res. 51:2138–2143.[Abstract/Free Full Text]
9. Liotta LA, Steeg PS, Stetler-Stevenson WG. 1991 Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell. 64:327–336.[CrossRef][Medline]
10. Zucker S, Lysik RM, Zarrabi MH, Moll U. 1993 Mr 92,000 type IV collagenase is increased in plasma of patients with colon cancer and breast cancer. Cancer Res. 53:140–146.[Abstract/Free Full Text]
11. Ballin M, Comez SE, Sinha CC, Thorgeirsson UP. 1988 Ras oncogene mediated induction of a 92 kDa metalloproteinase; strong correlation with the malignant phenotype. Biochem Biophys Res Commun. 154:823–838.
12. Bernhard ED, Gruber SB, Muschel RJ. 1994 Direct evidence linking expression of matrix metalloproteinase 9 (92-kDa gelatinase/collagenase) to the metastatic phenotype in transformed rat embryo cells. Proc Natl Acad Sci USA. 91:4293–4297.[Abstract/Free Full Text]
13. Hua J, Muschel R. 1996 Inhibition of matrix metalloproteinase 9 expression by a ribozyme blocks metastasis in a rat sarcoma model system. Cancer Res. 56:5279–5284.[Abstract/Free Full Text]
14. Nakajima M, Welch D, Wynn D, Tsuruo Y, Nocolson G. 1993 Serum and plasma M(r) 92,000 progelatinase levels correlate with spontaneous metastasis of rat 13762NF mammary adenocarcinoma. Cancer Res. 53:5802–5807.[Abstract/Free Full Text]
15. Watanabe H, Nakanishi I, Yamashita K, Hayakawa T, Okada Y. 1993 Matrix metalloproteinase-9 (92 kDa gelatinase/type IV collagenase) from U937 monoblastoid cells: correlation with cellular invasion. J Cell Sci. 104:991–999.[Abstract]
16. Kossakowska AE, Huchcroft SA, Urbanski SJ, Edwards DR. 1996 Comparative analysis of the expression patterns of metalloproteinases and their inhibitors in breast neoplasia, sporadic colorectal neoplasia, pulmonary carcinomas and malignant non-Hodgkin’s lymphomas in humans. Br J Cancer. 73:1401–1408.[Medline]
17. Sang QXA. 1998 Complex role of matrix metalloproteinases in angiogenesis. Cell Res. 8:171–177.[Medline]
18. Jackson CJ, Nguyen M. 1997 Human microvascular endothelial cells differ from macrovascular endothelial cells in their expression of matrix metalloproteinases. Int J Biochem Cell Biol. 29:1167–1177.[CrossRef][Medline]
19. Anand-Apte B, Pepper MS, Voest E, et al. 1997 Inhibition of angiogenesis by tissue-inhibitor of metalloproteinase-3. Opthalmol Vis Sci. 38:817–823.
20. Takigawa MY, Nishida Y, Suzuki F, Kishi J, Yamashita K, Hayakawa T. 1990 Induction of angiogenesis in chick yolk sac membrane by polyamines and its inhibition by tissue inhibitor of metalloproteinases (TIMP-1 and TIMP-2). Biochem Biophys Res Commun. 171:1264–1271.[CrossRef][Medline]
21. Talbot DC, Brown PD. 1996 Experimental and clinical studies on the use of matrix metalloproteinase inhibitors for the treatment of cancer. Eur J Cancer. 32:2528–2533.[CrossRef]
22. Lozonschi L, Sunamura M, Kobari M, Egawa S, Ding L, Matsuno S. 1999 Controlling tumour angiogenesis and metastasis of C26 murine colon adenocarcinoma by a new matrix metalloproteinase inhibitor, KB-R7785, in two tumour models. Cancer Res. 59:1252–1258.[Abstract/Free Full Text]
23. Patterson BC, Sang QA. 1997 Angiostatin-converting enzyme activities of human matrilysin and gelatinase B/type IV collagenase. J Biol Chem. 272:28823–28825.[Abstract/Free Full Text]
24. Hanahan D, Folkman J. 1996 Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 86:353–364.[CrossRef][Medline]
25. Kawamoto H, Uozumi T, Kawamtot K, Arita K, Yano T, Hirohata T. 1996 Type IV collagenase activity and cavernous sinus invasion in human pituitary adenomas. Acta Neurochir. 138:390–395.[CrossRef][Medline]
26. Turner HE, Stratton IM, Byrne JV, Adams CBT, Wass JAH. 1999 Audit of selected patients with non-functioning pituitary adenomas treated without irradiation—a follow-up study. Clin Endocrinol. 51:281–284.[CrossRef][Medline]
27. Bates AS, Farrell WE, Bicknell EJ, et al. 1997 Allelic deletion in pituitary adenomas reflects aggressive biological activity and has potential value as a prognostic marker. J Clin Endocrinol Metab. 82:818–824.[Abstract/Free Full Text]
28. Turner HE, Nagy ZS, Gatter KC, Esiri MM, Wass JAH, Harris AL. 2000 Proliferation, Bcl-2 expression and angiogenesis in pituitary adenomas—relationship to tumour behaviour. Br J Cancer. In press.
29. Schecter J, Ahmad N, Weiner R. 1988 Activation of anterior pituitary folliculostellate cells in the formation of estrogen-induced prolactin-secreting tumours. Neuroendocrinology. 48:569–576.[Medline]
30. Schecter J, Weiner R. 1991 A model for the role of basic fibroblast growth factor in pituitary tumourogenesis. Ann NY Acad Sci. 638:503–504.[CrossRef][Medline]
31. Vu TH, Werb Z. 1998 Gelatinase B: structure, regulation and function. In: Parks WC, Mecham RP, eds. Matrix metalloproteinases. San Diego: Academic Press; 115–148.
32. Ring P, Johansson K, Moyhtya M, Rubin K, Lindmark G. 1997 Expression of tissue inhibitor of metalloproteinases TIMP-2 in human colo-rectal cancer—a predictor of tumour stage. Br J Cancer. 76:805–811.[Medline]
33. Linn R, DuPont BR, Knight CB, Plaetke R, Leach RJ. 1996 Reassignment of the 92 kDa type IV collagenase gene (CLG4B) to human chromosome 20. Cytogenet Cell Genet. 72:159–161.[Medline]
34. Vu TH, Shipley JM, Bergers G, et al. 1998 MMP9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell. 93:411–422.[CrossRef][Medline]
35. Tamura T, Nakanishi T, Kimura Y, et al. 1996 Nitric oxide mediates interleukin-1-induced matrix degradation and basic fibroblast growth factor release in cultured rabbit articular chondrocytes: a possible mechanism of pathological neovascularisation in arthritis. Endocrinology. 137:3729–3737.[Abstract]
36. Bian J, Sun Y. 1997 Transcriptional activation by p53 of the human type IV collagenase promoter. Mol Cell Biol. 17:6330–6338.[Abstract]
37. Oda N, Abe M, Sato Y. 1999 ETS-1 converts endothelial cells to the angiogenic phenotype by inducing the expression of matrix metalloproteinases and integrin ß3. J Cell Physiol. 178:121–132.[CrossRef][Medline]
38. Sehgal I, Thompson TC. 1998 Neuropeptides induce Mr 92,000 type IV collagenase (matrix metalloprotease-9) activity in human prostate cancer cell lines. Cancer Res. 58:4288–4291.[Abstract/Free Full Text]
39. Beitner-Johnson D, Millhorn DE. 1998 Hypoxia induces phosphorylation of the cAMP response element binding protein by a novel signalling mechanism. J Biol Chem. 273:19834–19839.[Abstract/Free Full Text]
40. Kvietikova I, Wenger RH, Marti HH, Gassmann M. 1995 The transcription factors ATF-1 and CREB-1 bind constitutively to the HIF-1 DNA recognition site. Nucleic Acids Res. 23:4542–4550.[Abstract/Free Full Text]
41. Herber B, Truss M, Beato M, Muller R. 1994 Inducible regulatory elements in the human cyclin D1 promoter. Oncogene. 9:1295–1304.[Medline]

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