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[Cancer Research 62, 5405-5407, October 1, 2002]
© 2002 American Association for Cancer Research

Advances in Brief

Celecoxib, a Selective Cyclooxygenase 2 Inhibitor, Protects against Human Epidermal Growth Factor Receptor 2 (HER-2)/neu-induced Breast Cancer1

Louise R. Howe2, Kotha Subbaramaiah, Jay Patel, Jaime L. Masferrer, Aparna Deora, Clifford Hudis, Howard T. Thaler, William J. Muller, Baoheng Du, Anthony M. C. Brown and Andrew J. Dannenberg

Departments of Cell and Developmental Biology [L. R. H., A. M. C. B.] and Medicine [K. S., B. D., A. J. D.], Weill Medical College of Cornell University, New York, New York 10021; Strang Cancer Research Laboratory at the Rockefeller University, New York, New York 10021 [L. R. H., K. S., J. P., A. M. C. B., A. J. D.]; Pharmacia Corporation, St. Louis, Missouri 63017 [J. L. M., A. D.]; Departments of Medicine [C. H.] and Epidemiology and Biostatistics [H. T. T.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021; and McGill University, Montreal, Quebec, Canada [W. J. M.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Cyclooxygenase 2 (HER-2) (Cox-2), an inducible form of Cox, is overexpressed in HER-2/neu-positive human breast cancers. The aim of this study was to determine whether celecoxib, a selective Cox-2 inhibitor, protected against HER-2/neu-induced experimental breast cancer. Cox-2 protein was detected in breast carcinomas from mouse mammary tumor virus (MMTV)/neu mice. Treatment with celecoxib (500 ppm) significantly reduced the incidence of mammary tumors in MMTV/neu mice (P = 0.003) and caused about a 50% reduction in mammary prostaglandin E2 (PGE2) levels. Because mammary glands from MMTV/neu mice expressed all four PGE2 receptor subtypes, we speculate that signaling through PGE2 receptors is important for mammary tumorigenesis. These results strengthen the rationale for developing clinical trials to determine whether selective Cox-2 inhibitors possess anticancer properties in humans at risk for breast cancer.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
The HER-23 gene (also called c-erbB2 and neu) encodes a 185 kDa transmembrane receptor tyrosine kinase that belongs to the family of receptors for epidermal growth factor. Amplification and/or overexpression of HER-2/neu is found in multiple human cancers, including 20–30% of breast cancers (1) . Overexpression of HER-2/neu in breast cancer is associated with a poor prognosis for the patient (2) . Treatment with trastuzumab (Herceptin), a humanized anti- HER-2/neu monoclonal antibody, has proven to be of benefit to patients with HER-2/neu-overexpressing breast tumors (3) . Despite this significant advance, new therapeutic approaches are needed to prevent or treat HER-2/neu-overexpressing malignancies.

Cox-2, an inducible enzyme that catalyzes the synthesis of PGs, is widely regarded as a potential pharmacological target for preventing and possibly treating gastrointestinal malignancies (4, 5, 6) . Importantly, there is growing evidence that Cox-2 may also be important for mediating HER-2/neu-induced mammary tumor formation. Two recent studies found increased levels of Cox-2 in HER-2/neu-overexpressing human breast cancers (7 , 8) . High levels of Cox-2 correlated significantly with reduced survival (8) . A cause-and-effect relationship between Cox-2 expression and mammary tumor induction was demonstrated in a recent study, which showed that forced overexpression of Cox-2 in murine mammary gland was sufficient to induce breast cancer in multiparous animals (9) . In addition to the genetic evidence implicating Cox-2 in breast tumor formation, selective Cox-2 inhibitors reduce the formation and growth of chemically induced breast cancers (10 , 11) .

Given the observed relationship between HER-2/neu and Cox-2 expression in human breast cancers (7 , 8) , it is important to investigate the effects of a selective Cox-2 inhibitor in a relevant animal model. Accordingly, the main purpose of the current study was to determine whether treatment with celecoxib, a selective Cox-2 inhibitor, delayed the onset of HER-2/neu-induced mammary tumors. For this experiment, we selected a mouse strain in which wild-type neu is overexpressed in the mammary gland under the control of the MMTV long terminal repeat. Mice overexpressing wild-type neu develop focal mammary tumors after a long latency period (12) . At least 65% of these tumors carry somatic activating mutations in the neu transgene, which resemble an alternatively spliced HER-2/neu isoform detected in human breast tumors (13 , 14) . We found that Cox–2 was expressed in mammary glands and tumors derived from MMTV/neu mice, and that treatment with celecoxib reduced the incidence of mammary tumors in this model.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Reagents and Chemicals.
Celecoxib (SC-58635; 4-[5-(4-methylphenyl)-3-trifluoromethyl)-1H-pyrazol-1-yl]benzene-sulfonamide) was supplied by Pharmacia Corporation (St. Louis, MO).

Mouse Experimental Procedure.
MMTV/neu transgenic mice [FVB/N-TgN(MMTVneu)202Mul] were obtained from Jackson Laboratory and bred to produce multiple litters. Females were randomly assigned to one of two groups at weaning: control (n = 26) or treatment (n = 24) groups, which were fed Laboratory Autoclavable Rodent Diet 5010 ad libitum. The diet of mice in the treatment group was supplemented with 500 ppm celecoxib. Mice were palpated twice weekly for mammary gland tumor nodules, and the time of appearance of the first tumor (latency period) was recorded. Animals were sacrificed when tumors were 1 cm in diameter, or at 1 year of age, and the number of tumors of at least 0.5 cm diameter was scored. There was no evidence of toxicity in the drug-treated animals. At the time of sacrifice, body weights were similar in the control (26.5 ± 1.4 g) and drug-treated animals (26.8 ± 2.2 g). Mammary tissues were harvested from sacrificed animals, snap-frozen in liquid nitrogen and stored at -80°C. Tissue was also formalin-fixed and paraffin-embedded. Tumors were confirmed by histological evaluation.

Analysis of Cox-2 Protein.
Cox-2 protein in mammary glands and tumors was assayed using a coupled immunoprecipitation/immunoblotting assay, as previously described (15) , with the following modifications: 5 mg of mammary tissue were used for lysate preparation, and 20 µl of rabbit anti-Cox-2 antiserum were used in the immunoprecipitation step (Santa Cruz Biotechnology, Inc., Santa Cruz, CA).

Determination of PGE2 Levels.
Resected mammary glands were homogenized and PGs extracted as described previously (16) . PGE2 was assayed using an enzyme-linked immunosorbent assay kit (Cayman Chemicals, Ann Arbor, MI).

Assay of Celecoxib Levels.
Serum was collected by retro-orbital bleeding from 18 animals fed 500 ppm celecoxib, and levels of celecoxib assayed by liquid chromatography/mass spectrometry.

Analysis of EP Expression.
Expression of EP in mouse mammary gland was analyzed by RT-PCR. RNA was prepared from mammary gland tissue (20 mg) using the RNeasy total RNA isolation kit (Qiagen, Valencia, CA), and cDNA generated from 1 µg of RNA using oligodeoxythymidylic acid and Murine Leukemia Virus reverse transcriptase. PCR primers for individual EP receptors have been described previously (17 , 18) . The identity of each PCR product was confirmed by DNA sequencing.

Statistical Analysis.
A log-rank test for comparing survival-type data between groups was used to compare tumor incidence in the control and drug-treated cohorts. All other data sets (shown as mean ± SD, unless otherwise stated) were evaluated for statistical significance using a t test.


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Before investigating the potential therapeutic benefits of a selective Cox-2 inhibitor, it was first necessary to determine whether Cox-2 was expressed in breast tissues derived from MMTV/neu mice. As shown in Fig. 1Citation , Cox-2 protein was present in tumors from MMTV/neu mice and also in MMTV/neu nontumorous mammary glands (Fig. 1)Citation . Since mammary tissues from MMTV/neu mice express Cox-2, this strain was considered a suitable model to evaluate the potential anticancer properties of a selective Cox-2 inhibitor.



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  		Fig. 1. Cox-2 is expressed in neu-induced mammary tumors. Immunoblot analysis was performed on protein derived from nontumorous mammary glands (MGs; Lanes 2–4) and mammary tumors (Lanes 5–7) derived from MMTV/neu mice. Lane 1 shows a Cox-2 standard (Std). The blot was probed with anti-Cox-2 antibody.

 
To determine whether celecoxib inhibited HER-2/neu-induced mammary tumorigenesis, we compared tumor incidence in female MMTV/neu mice fed either control diet or diet containing 500 ppm celecoxib. Treatment with celecoxib inhibited the development of mammary tumors (Fig. 2)Citation . Thus, mammary tumors were detected in 50% of animals fed control diet by 32.3 weeks of age versus 39.6 weeks of age in celecoxib-treated mice (T50 = 32.3 weeks versus T50 = 39.6 weeks; P = 0.003; Fig. 2Citation ). At all subsequent ages, the incidence of mammary tumors was also reduced in celecoxib-treated mice relative to control mice (Fig. 2)Citation . Consistent with this protective effect of celecoxib, tumor multiplicity was similar in the two groups (control, 1.38 ± 0.62; celecoxib, 1.25 ± 1.01), despite the fact that the celecoxib-treated mice were generally older at the time of sacrifice. To ensure that this protective effect of celecoxib occurred at concentrations of drug that can be safely achieved in humans, serum celecoxib levels were measured. Levels of celecoxib in the sera of drug-treated mice ranged from 0.7 to 8.8 µM (mean, 2.4 µM), which is within the range reported to inhibit inflammation and PG biosynthesis in humans.



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  		Fig. 2. Celecoxib retards neu-induced mammary tumorigenesis. Female MMTV/neu transgenic mice were fed control diet or diet containing 500 ppm celecoxib from weaning onwards. Mammary tumor incidence was significantly delayed in the 500 ppm cohort (P = 0.003, log-rank test).

 
A substantial body of evidence suggests that the antitumor activity of Cox inhibitors can be attributed, at least in part, to inhibition of PG biosynthesis (4) . Moreover, previous studies have suggested a role for PGE2 in mammary tumorigenesis (19 , 20) . It was of interest, therefore, to determine amounts of PGE2 in mammary glands harvested from control versus celecoxib-treated mice. As shown in Fig. 3Citation , levels of PGE2 were reduced by nearly 50% in the mammary glands of mice treated with celecoxib (14.3 ng/g in control versus 7.6 ng/g in celecoxib-treated mice; P < 0.02). PGE2 elicits cellular responses via interaction with four cell-surface receptors, EP1–4 (21) . RT-PCR was carried out to determine which receptors were expressed in the mammary glands of MMTV/neu mice. Each of the four known EP receptors was expressed in the mammary glands of these mice (Fig. 4)Citation .



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  		Fig. 3. Celecoxib reduces mammary PGE2 levels. Levels of PGE2 were measured in mammary glands harvested from mice fed control diet or mice fed diet supplemented with celecoxib using an enzyme-linked immunosorbent assay. Celecoxib (500 ppm) was sufficient to cause a significant reduction in amounts of PGE2 (*, P < 0.02). Data are shown as mean + SE, n = 10/group.

 


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  		Fig. 4. Expression of EP subtypes in mammary glands of MMTV/neu mice. The expression of EP receptors was analyzed in nontumorous mammary glands from three female nulliparous MMTV/neu mice by RT-PCR. All four receptor subtypes were detected in each of the three mammary glands tested (Lanes 1–3). No bands were observed when cDNA was omitted from the PCR reaction (Lane 4) or when reverse transcriptase enzyme was not included in the reverse transcriptase reaction (data not shown).

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
The main goal of the current experiments was to determine whether a selective Cox-2 inhibitor suppressed mammary tumorigenesis in a relevant animal model of breast cancer. Given the recent discovery that Cox-2 is overexpressed in HER-2/neu-positive human breast cancers (7 , 8) , it was logical to use MMTV/neu mice. Importantly, we first established that Cox-2 was expressed in mammary tissues derived from these mice. This finding provided a rationale for investigating the chemopreventive activity of celecoxib in this model.

The fact that a clinically relevant concentration of celecoxib caused a significant delay in the onset of mammary tumors raises important issues. Certainly, it suggests a potential role for using selective Cox-2 inhibitors to prevent human breast cancer. For example, because both HER-2/neu and Cox-2 are commonly overexpressed in ductal carcinoma in situ (22) , it would be reasonable to evaluate the potential anticancer properties of a selective Cox-2 inhibitor alone or with a HER-2 inhibitor in that patient population. Observational studies show a clear correlation between NSAID use and reduced risk of colorectal cancer (4) . Although some epidemiological studies suggest that NSAIDs protect against breast cancer (19) , the results are less clear than for colon cancer. The fact that Cox-2 is undetectable in many HER-2/neu-negative tumors (7 , 8) may help to explain why NSAIDs have not been shown consistently to protect against breast cancer. On the basis of the current results, future epidemiological studies should attempt to determine whether the efficacy of NSAIDs as protective agents varies according to the HER-2/neu status of a tumor.

There is considerable evidence that Cox-2-derived PGs are protumorigenic. PGs have been shown to stimulate cell proliferation, inhibit apoptosis, induce angiogenesis, and suppress immune surveillance (4 , 6 , 15) . Additionally, PGE2 was recently found to increase activity of the estrogen synthase aromatase (23) . Thus, it is possible that PG-mediated stimulation of estrogen synthesis may be an important organ site-specific consequence of Cox-2 up-regulation in breast tissue. We showed that celecoxib caused nearly a 50% reduction in amounts of PGE2 in mammary tissue. Given the recognized link between PGs and tumorigenesis, it is reasonable to conclude that the selective Cox-2 inhibitor suppressed mammary tumor formation, at least in part, by inhibiting PG biosynthesis.

PGE2 exhibits biological activity through binding to G-protein-coupled receptors. Four PGE2 receptor subtypes, EP1–4, have been identified (21) . Because of the recognized importance of PGs in carcinogenesis, the potential role of individual receptors in mediating tumorigenesis is being actively investigated. In one recent study, homozygous deletion of EP2 caused a decrease in the number and size of intestinal polyps in a mouse model of human familial adenomatous polyposis (24) . We show for the first time that all four EP receptors are expressed in mammary tissue. Notably, an EP1 receptor antagonist has been reported to decrease the incidence of chemically induced breast cancer in rats (25) . Because we detected expression of all four receptor subtypes in mammary glands from MMTV/neu mice, it will be interesting to determine which receptor(s) contributes to HER-2/neu-induced breast cancer.

It is also worth considering the potential implications of this study for the treatment of breast cancer. Simultaneous targeting of Cox-2 and HER-2/neu, using celecoxib and anti-HER-2 antibodies, has been shown to inhibit experimental colorectal carcinoma growth more effectively than either agent alone (26) . By analogy, selective Cox-2 inhibitors may enhance the efficacy of trastuzumab in the treatment of HER-2/neu-overexpressing breast cancers.


   ACKNOWLEDGMENTS
 
We thank Dr. Jack Fishman for helpful discussions, Dr. Hai Nguyen for pathological analysis, and K. Tolle and B. Zweifel for technical assistance.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by NIH Grant CA89578 and the Colin Foundation. Back

2 To whom requests for reprints should be addressed, at Strang Cancer Research Laboratory, 1230 York Avenue, Box 231, New York, NY 10021. E-mail: lrhowe{at}med.cornell.edu Back

3 The abbreviations used are: HER-2, human epidermal growth factor receptor 2; Cox, cyclooxygenase; PG, prostaglandin; PGE2, prostaglandin E2; EP, PGE2 receptor; MMTV, mouse mammary tumor virus; NSAID, nonsteroidal anti-inflammatory drug; RT-PCR, reverse transcriptase-coupled PCR. Back

Received 7/ 8/02. Accepted 8/15/02.


   REFERENCES
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
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Levels of Cyclooxygenase-2 Are Increased in the Oral Mucosa of Smokers: Evidence for the Role of Epidermal Growth Factor Receptor and Its Ligands
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B. A. Narayanan, N. K. Narayanan, B. Pittman, and B. S. Reddy
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A.-M. Simeone, Y.-J. Li, L. D. Broemeling, M. M. Johnson, M. Tuna, and A. M. Tari
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Cyclooxygenase-2 and Microsomal Prostaglandin E Synthase-1 Are Overexpressed in Squamous Cell Carcinoma of the Penis
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Elevated Cyclooxygenase-2 Expression Is Associated with Altered Expression of p53 and SMAD4, Amplification of HER-2/neu, and Poor Outcome in Serous Ovarian Carcinoma
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Regulation of Cyclooxgenase-2 mRNA Stability by Taxanes: EVIDENCE FOR INVOLVEMENT OF p38, MAPKAPK-2, and HuR
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