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Carcinogenesis Advance Access originally published online on August 3, 2006
Carcinogenesis 2007 28(1):130-135; doi:10.1093/carcin/bgl140
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© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Characterization of a preclinical model of simultaneous breast and ovarian cancer progression

Alison Y. Ting1,2, Bruce F. Kimler1,4, Carol J. Fabian1,3 and Brian K. Petroff1,3,5,*

1 Breast Cancer Prevention Center, University of Kansas Medical Center Kansas City, KS 66160, USA
2 Department of Molecular and Integrative Physiology, University of Kansas Medical Center Kansas City, KS 66160, USA
3 Department of Internal Medicine, University of Kansas Medical Center Kansas City, KS 66160, USA
4 Department of Radiation Oncology, University of Kansas Medical Center Kansas City, KS 66160, USA
5 Center for Reproductive Sciences, University of Kansas Medical Center Kansas City, KS 66160, USA

*To whom correspondence should be addressed. Email: bpetroff{at}kumc.edu


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Women at increased risk for breast cancer are often also at increased risk for ovarian cancer, reflecting common risk factors and intertwined etiologies for both diseases. Unlike breast cancer prevention, primary ovarian cancer prevention has been impractical due to the low incidence, lack of risk and response biomarkers and difficulties in sampling ovarian tissue. Challenges in the development of ovarian cancer prevention drugs, however, may be circumvented through the development of breast cancer prevention strategies that simultaneously decrease ovarian cancer. In the present study, three commonly used mammary cancer carcinogen models [7,12-dimethylbenz[{alpha}]anthracene (DMBA), N-methyl-N-nitrosourea (MNU) and estradiol (E2)] were combined with local ovarian DMBA administration to induce progression to mammary and ovarian cancer concurrently in the rat. Animals were treated for 3 or 6 months, and tissue histology as well as proliferation, hormonal and inflammation biomarkers were assessed. Mammary and ovarian morphologies (measured as descriptive histology and dysplasia scores) were normal in vehicle controls. Mammary hyperplasia was observed in DMBA/DMBA (mammary carcinogen/ovarian carcinogen) and MNU/DMBA-treated rats; however, ovarian preneoplastic changes were seldom observed after these treatments. All E2/DMBA-treated rats had mammary hyperplasia, atypia, ductal carcinoma in situ and/or invasive adenocarcinoma, while 50% also developed preneoplastic changes in the ovary (ovarian epithelial and stromal hyperplasia and inclusion cyst formation). In both the mammary gland and ovary, decreased estrogen receptor alpha expression was detected, and in the mammary gland elevated Ki-67 and cyclooxygenase-2 expressions were observed. This combined breast and ovarian cancer rat model (systemic E2 treatment and local ovarian DMBA) may be useful for future dual target breast and ovarian cancer prevention studies.

Abbreviations: COX-2, cyclooxygenase-2; DMBA, 7,12-dimethylbenz[{alpha}]anthracene; E2, 17ß-estradiol; EOC, epithelial ovarian cancer; H&E, hematoxylin & eosin; MNU, N-methyl-N-nitrosourea


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Breast cancer chemoprevention trials are facilitated by minimally invasive techniques to sample breast tissue and the availability of a number of surrogate biomarkers to evaluate prevention drugs in phase II trials as well as the high incidence of this disease in phase III trials (1–3). In contrast, sampling of ovarian tissue is invasive and appropriate biomarkers for ovarian cancer prevention trials are controversial (4). Additionally, ovarian cancer is a relatively uncommon disease making testing of drugs for primary prevention difficult to justify. One possible solution is to develop breast cancer chemoprevention drugs that simultaneously prevent ovarian cancer. Indeed, successful human ovarian cancer chemoprevention has only been demonstrated incidentally during the course of breast cancer prevention trials (i.e. fenretinide) (5). An initial obstacle to the development of dual target breast and ovarian cancer prevention drugs is the absence of an appropriate animal model.

Rats are the most frequently used animal model for breast cancer chemoprevention, particularly chemical [7,12-dimethylbenzanthracene (DMBA) and N-methyl-N-nitrosourea (MNU)] or hormonal [17ß-estradiol (E2)] carcinogen models (6–8). In intact females, these carcinogens induce a high incidence of mammary adenocarcinomas (MACs) that express similar histology and biomarker expressions to the human disease within 2–5 months (6–8). No commonly used preclinical model of ovarian cancer has been used to test prevention drugs, but one promising method of inducing epithelial ovarian cancer (EOC) is the direct application of DMBA to the ovarian surface epithelium. This local ovarian DMBA treatment results in an ~30–40% occurrence of EOC and a greater incidence of preneoplastic changes in the ovary (9–11). In this study, these breast and ovarian cancer models were tested in combination in an effort to develop the first preclinical model of simultaneous breast and ovarian cancer progression.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Animals and treatments
Female Fischer 344 rats (Harlan Breeding Laboratories, Indianapolis, IN, n = 6–8 per treatment x time group) weighing 50–55 g were housed three per cage in a climate and light (12L:12D) controlled environment, and received food and water ad libitum. All experimental protocols were approved by the University of Kansas Medical Center Animal Care and Use Committee. Within a week of arrival, rats were anesthetized using ketamine hydrochloride (80 mg/kg), atropine sulfate (0.2 mg/kg) and xylazine (8 mg/kg). Hemiovariectomy was performed aseptically in order to concentrate ovulation upon the treated ovary and hasten a senescent hormonal milieu (12,13). In addition to increasing ovulation rate on the remaining ovary, Anzalone et al. (12) have shown that hemiovariectomy mimics age-related alterations such as a lower incidence of regular cyclicity altered magnitude of the proestrous LH surge as well as reduced ovarian follicular reserve when compared with age-matched intact rats. The remaining ovary was treated by passing a DMBA-impregnated (2.5 mm region dipped in melted DMBA) or vehicle 5–0 silk suture through the ovary twice such that the DMBA or vehicle region was apposed directly and gently secured to the ovarian surface epithelium. Local ovarian DMBA application ultimately results in a 30–50% incidence of ovarian cancer arising from the surface epithelium within 12 months using this model (9–11). Rats receiving ovarian DMBA were subsequently treated with mammary carcinogens: DMBA (10 mg/kg, p.o.), MNU (50 mg/kg, i.p.), or 17ß-estradiol (E2, 3.0 mg, pellet implant; Hormone Pellet Press, Leawood, KS). Rats (n = 12) receiving vehicle-coated sutures were further treated with vehicle (corn oil; 4 ml/kg, p.o.; blank implants s.c.).

Tissue preparation
Rats were killed at 3 or 6 months post-treatment, and serum was collected and stored at –80°C. Right thoracic mammary glands were excised, fixed in 4% paraformaldehyde (PFA) and embedded in paraffin. Right abdominal-inguinal mammary glands were spread out onto a glass slide, fixed in 4% PFA and infused with alum carmine following a whole mount preparation protocol (14). The ovary was bisected through the site of DMBA application. One half was fixed in 4% PFA and embedded in paraffin while the remainder was snap-frozen for future study.

Immunohistochemistry
Six micrometer sections of mammary glands and ovaries were deparaffinized, rehydrated and stained with hematoxylin & eosin (H&E). H&E sections were evaluated for premalignant morphological changes associated with MAC and EOC progression (10,15) by an observer blinded to treatment groups. Additional sections were prepared for immunostaining by antigen retrieval (92.78°C, 10 mM citrate buffer, 25 min) and incubation with 0.3% hydrogen peroxide (Lab Vision, Fremont, CA). Non-immune serum or primary antibodies against estrogen receptor alpha (ER; 1:100; Clone SP1; rabbit monoclonal antibody; Lab Vision), cyclooxygenase-2 (COX-2; 1 : 50; RB-9072; rabbit polyclonal antibody; Lab Vision) and Ki-67 (1 : 25; Clone Ki-S5; mouse monoclonal antibody; Dako, Carpinteria, CA) were applied and visualized with DAB chromogen and biotinylated secondary antibodies. All incubations were carried using a Dako LV-1 autostainer.

Hormone assays
Serum concentrations of E2 were determined by ELISA according to manufacturer's protocol (DSL-10-4300, Diagnostic Systems Laboratories, Webster, TX). All samples were run within the same assay, and the intraassay CV was <10%.

Quantitative analysis of preneoplastic lesions
H&E sections of the mammary gland and ovary were evaluated for pre-neoplastic and neoplastic morphological changes associated with MAC and EOC progression (10,15). Mammary tissue was evaluated for preneoplastic changes including mild or severe ductal hyperplasia and hyperplasia with atypia as well as neoplastic changes such as ductal carcinoma in situ (DCIS) and invasive DC, corresponding to scores of 1–5, respectively. A score of 0 was given to animals with normal mammary histology. Pre-neoplastic changes of the ovary were defined as surface (bursal flat) hyperplasia, inclusion cysts, stromal hyperplasia and papilloma. Scores of 0, 1 and 2 were given to each section according to the severity or the prevalence of each pre-neoplasic category (a score of 0 represents an absence of preneoplastic changes and a score of 2 indicates a high degree of abnormality). Sections from three different levels of the ovary from each animal were evaluated. These preneoplastic criteria are the same as those used by Stewart et al. (10) with this rat model of ovarian carcinogenesis.

Ki-67 and ER expression in the mammary ductal epithelia cells and ovarian surface epithelia and COX-2 expression in ovarian epithelia were quantified by counting immunoreactive epithelial cells and total epithelial cells (at least 1000 cells were evaluated per section). The intensity of COX-2 immunostaining in the mammary gland was quantified with an automated cellular imaging system (ChromaVision, San Juan Capistrano, CA) (16). Three random fields of each tissue section were selected for quantification (combined area evaluated = 1.56 mm2), and the staining intensity was expressed as percent area occupied by COX-2-immunoreactive cells.

All continuous values are presented as the mean ± SEM, and their statistical comparisons were made using two-way analysis of variance (StatView). Differences were considered significant when P ≤ 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Histopathology
Mammary gland whole mounts
In the mammary gland, DMBA, MNU and E2 treatment increased ductal branching and area occupied by alveoli by 3 months, and the impact of E2 was the most extensive among these three carcinogens. These effects were further increased after 6 months of treatment (Figure 1B–D). Vehicle-treated rats (3 and 6 months) showed normal mammary morphology (Figure 1A).


Figure 1
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  		Fig. 1 Whole mounts (A–D) and mammary (E–H) and ovarian histology (I–L). DMBA/DMBA (systemic/ovarian) treated rats (B, F and J) and MNU/DMBA-treated rats (C, G and K) showed increased ductal branching in whole mounts (B and C), increased alveoli in H&E sections (F and G) and absence of preneoplastic changes in the ovary (J and K). All E2/DMBA-treated rats developed mammary preneoplastic or neoplastic changes (D and H), and 50% of them also showed ovarian preneoplastic changes (L; insert: magnified image of an inclusion cyst). Scale bars = 1 mm (A–D), 200 µm (E–L) and 50 µm (L insert). Abbreviation: F = ovarian follicle, CL = corpus luteum, Su = suture material, HYP = epithelial hyperplasia, IC = inclusion cyst.

 
Mammary histology
Vehicle-treated (3 and 6 months) and systemic DMBA-treated (3 months) rats displayed normal histology showing scattered acini throughout the mammary gland, each bearing a single layer of ductal epithelial cells surrounded by myoepithelial cells (Figure 1E). Increased dysplasia scores were observed in carcinogen-treated animals (Table I). Ductal hyperplasia was observed in some DMBA/DMBA- and MNU/DMBA-treated rats (3 and 6 months) and in all 3-month E2/DMBA-treated rats (Figure 1F and G). Six months of systemic E2 induced ductal hyperplasia (2/6), DCIS (3/6), and invasive adenocarcinoma (1/6) (Figure 1H).


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  		Table I Mammary and ovarian dysplasia scores and serum E2 concentrations

 
Ovarian histology
Local ovarian DMBA application caused increased ovarian dysplasia and benign abnormalities such as local inflammation around suture materials, mild stromal hyperplasia and decreased follicle numbers (Figure 1J and K and Table I). Combined systemic E2 and ovarian DMBA treatment further induced ovarian preneoplastic changes of epithelial origin in 50% rats (i.e. epithelial hyperplasia and inclusion cyst) following 6 month treatment (Figure 1L and Table I). Vehicle-treated rats showed normal ovarian histology with mild inflammation induced by suture materials (Figure 1I).

Epithelial proliferation was stimulated by E2 treatment
Ki-67 expression was localized in the nucleus of ductal epithelial cells in the mammary gland and surface epithelial cells in the ovary. Following 6 month treatment, Ki-67-immunoreactive cells were increased in E2/DMBA mammary glands when compared with controls and other carcinogen-treated rats (Figure 2A–C; P ≤ 0.05). Ovarian epithelial staining for Ki-67 increased significantly from 3 to 6 months in rats treated with E2/DMBA (P ≤ 0.05) but did not differ significantly from controls and other carcinogen-treated rats.


Figure 2
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  		Fig. 2 Mammary epithelial proliferation (Ki-67) was increased above controls at 6 months in E2/DMBA-treated group (A and C) when compared with controls (B; P ≤ 0.05). Percentage COX-2 expression in mammary gland also increased in E2/DMBA-treated groups (F) as compared with controls (E) and other carcinogen-treated groups following 3 and 6 month treatment (D; P ≤ 0.05). Arrows indicate positively stained mammary epithelial cells. Scale bars = 100 µm. For A and D, different letters indicate significant difference among different treatment groups.

 
Mammary COX-2 expression increased in E2/DMBA-treated rats
COX-2 expression was elevated in the mammary gland of E2/DMBA-treated rats when compared with controls and other carcinogen-treated rats (3 and 6 months) (Figure 2D and E; P ≤ 0.05). Although COX-2 expression in the ovarian surface epithelia did not increase after carcinogen treatments, preneoplastic changes of epithelial origin in the ovary of E2/DMBA-treated rats showed strong immunoreactivity to COX-2 (Figure 3).


Figure 3
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  		Fig. 3 Inclusion cysts found in the ovary of E2/DMBA-treated ovary (adjacent section of Figure 1L insert) showed positive COX-2 expression. Scale bar = 50 µm. Non-immune control not shown.

 
ER expression decreased with carcinogen treatment
ER immunoreactivity in the mammary gland was decreased after 6 month systemic DMBA, MNU and E2 treatment (Figure 4A–C; P ≤ 0.05). Ovarian DMBA similarly decreased the ER expression in the ovarian surface epithelium by 6 months of treatment when compared with controls (Figure 4D–F; P ≤ 0.05).


Figure 4
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  		Fig. 4 ER expression was downregulated in the mammary gland (A–C) and ovary (D–F) of carcinogen-treated rats when compared with controls after 6 month treatment (P ≤ 0.05). Arrows indicate positively stained mammary epithelial cells. Scale bars = 100 µm. For A and D, different letters indicate significant difference among different treatment groups.

 
Serum E2 concentrations
The sustained release E2 treatment provided a consistent and sustained increase in serum E2 when compared with DMBA, MNU, or vehicle treatment (Table I; P ≤ 0.05). E2-related side effects including pituitary and uterine hyperplasia were observed in two animals. Although ovarian granulosal proliferation was observed (in addition to epithelial and stromal ovarian hyperplasia) in all E2/DMBA-treated rats, it was not considered a preneoplastic lesion for EOC when determining dysplasia scores.


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
Breast and ovarian cancer have interdependent risk factors, and women at increased risk for one of these cancers are often at risk for the other (17,18). While active clinical trials are common for the evaluation of breast cancer prevention drugs, ovarian cancer prevention trials are seldom attempted due to low incidence of the disease, relatively invasive procedures for tissue sampling and the lack of well-established serum or imaging-based biomarkers (4). A logical approach to ovarian cancer chemoprevention may be the development of breast cancer prevention drugs that simultaneously decrease the risk of ovarian cancer. Toward this end, the present study is intended to produce a preclinical model for the evaluation of simultaneous chemoprevention of breast and ovarian cancer.

Systemic E2 and local ovarian DMBA induced preneoplastic changes in breast and ovary of the rat as demonstrated by elevated Ki-67 and COX-2 expression in addition to histological analysis. Unlike systemic DMBA and MNU, systemic E2 appeared to contribute not only to mammary carcinogenesis but also to the initiation of ovarian neoplasia. This additive or synergistic effect of E2 merits further exploration. One possible explanation is that the proliferative effect of E2 may increase the mutation rate of ovarian surface epithelial cells (19) and therefore accelerate the incidence of ovarian preneoplastic changes. Similarly, Stewart et al. (10) reported that when combined with gonadotropin hormones, local ovarian DMBA induced more ovarian preneoplastic lesions compared with DMBA treatment alone.

In the present study, putative ovarian preneoplastic changes such as inclusion cysts, epithelial hyperplasia, papilloma and stromal hyperplasia were used to evaluate progression toward ovarian cancer instead of actual cancer incidences. These criteria are the same as those of Stewart et al. (10) in DMBA-induced ovarian adenocarcinomas of the rat. While the presence of inclusion cysts in older women is common (20) and controversy concerning whether inclusion cysts are a preneoplastic lesion remains, many groups agree that ovarian inclusion cysts are a precursor for ovarian adenocarcinoma (21,22). Studies have shown that the number of inclusion cysts is increased in ovaries from patients with ovarian carcinoma, contralateral epithelial ovarian tumors or a family history of ovarian cancer compared with healthy subjects (23–26).

Elevated COX-2 expression has been observed in several tumors including ovarian neoplastic lesion (27–31). However, we found that overall ovarian epithelial COX-2 expression was not altered by E2/DMBA treatment, while COX-2 was highly expressed by ovarian inclusion cysts. Recent studies have also revealed the relevance of COX-1 expression in ovarian tumor development (11,32,33), suggesting another target for ovarian cancer chemoprevention, and its role should be investigated using this combined breast and ovarian cancer model.

Although this study was intended primarily to develop a practical model for the evaluation of dual target chemoprevention drugs against breast and ovarian cancer, our results also emphasize the interaction of the etiologies of ovarian and mammary cancer. Previous studies showed that latencies of breast tumor formation induced by MNU, DMBA and E2 in the rat are ~3, 4 and 6 months, respectively (34–37). However, systemic MNU and DMBA only caused precancerous mammary changes in the current experiment after 6 months of treatment. This is probably due to hemiovariectomy since the removal of both ovaries completely abolishes the ability of mammary carcinogens to induce mammary tumors (38). The intention of hemiovariectomy was to concentrate ovulation on the remaining treated ovary, which is a risk factor for human ovarian cancer (39,40). Approximately 50% of E2/DMBA-treated rats developed preneoplastic changes in the ovary. One way to further increase ovarian cancer progression might be to prolong the treatment [rats develop EOC from ovarian DMBA at 10–12 months (11)], but this is difficult due to advanced mammary tumor formation by 6 months of treatment. Additionally, our intention was to parallel the approach of human cancer prevention trials that focus on reversible or preventable preneoplasia and associated biomarkers rather than actual cancer incidence (3,41).

In the present study, we have demonstrated that rats treated with systemic E2 and local ovarian DMBA develop preneoplastic and neoplastic changes in the breast and ovary simultaneously. This model benefits from apparent additive or synergistic effects of E2 and DMBA in early ovarian carcinogenesis unlike models addressing breast or ovarian cancer separately. This approach is intended to facilitate the identification of promising cancer prevention drugs that simultaneously decrease progression to breast and ovarian cancer [e.g. postmenopausal SERMs or retinoids (5)] or reveal drugs that might incidentally decrease the incidence of one cancer while predisposing to the other [e.g. progesterone (42–45)]. While all women would potentially benefit from a well-tolerated chemoprevention drug against breast and ovarian cancer, a more conservative estimate of benefit in the United States might be the ~10% of the female population considered at elevated risk for these diseases.


   Acknowledgments
 
We would like to acknowledge Dr Sara Li, Dr Ossama Tawfik, Dr Kelli Valdez, Ms Qiao Xue, Mr Steve Gum and Ms Marilyn Davis for technical assistance. This project has been funded in part by the University of Alabama-Birmingham NCI Breast SPORE (NCI CA089019 [GenBank] ) and the Kansas Masonic Cancer Research Institute.

Conflict of Interest Statement: None declared.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received May 9, 2006; revised July 11, 2006; accepted July 21, 2006.


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