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Anthracene-Induced Mammary Tumors in Sprague–Dawley Rats

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Anthracene-Induced Mammary Tumors in Sprague–Dawley Rats Published OnlineFirst April 19, 2011; DOI: 10.1158/1940-6207.CAPR-10-0382 Cancer Prevention Research Article Research Apigenin Prevents Development of Medroxyprogesterone Acetate-Accelerated 7,12-Dimethylbenz(a)anthracene-Induced Mammary Tumors in Sprague–Dawley Rats Benford Mafuvadze1, Indira Benakanakere1, Franklin R. López Pérez2, Cynthia Besch-Williford2, Mark R. Ellersieck3, and Salman M. Hyder1 Abstract The use of progestins as a component of hormone replacement therapy has been linked to an increase in breast cancer risk in postmenopausal women. We have previously shown that medroxyprogesterone acetate (MPA), a commonly administered synthetic progestin, increases production of the potent angiogenic factor vascular endothelial growth factor (VEGF) by tumor cells, leading to the development of new blood vessels and tumor growth. We sought to identify nontoxic chemicals that would inhibit progestin-induced tumorigenesis. We used a recently developed progestin-dependent mammary cancer model in which tumors are induced in Sprague–Dawley rats by 7,12-dimethylbenz(a)anthracene (DMBA) treatment. The flavonoid apigenin, which we previously found to inhibit progestin-dependent VEGF synthesis in human breast cancer cells in vitro, significantly delayed the development of, and decreased the incidence and multiplicity of, MPA-accelerated DMBA-induced mammary tumors in this animal model. Whereas apigenin decreased the occurrence of such tumors, it did not block MPA- induced intraductal and lobular epithelial cell hyperplasia in the mammary tissue. Apigenin blocked MPA-dependent increases in VEGF, and suppressed VEGF receptor-2 (VEGFR-2) but not VEGFR-1 in regions of hyperplasia. No differences were observed in estrogen or progesterone receptor (ER/PR) levels, or the number of estrogen receptor–positive cells, within the mammary gland of MPA-treated animals administered apigenin, MPA-treated animals, and placebo treated animals. However, the number of progesterone receptor–positive cells was reduced in animals treated with MPA or MPA and apigenin compared with those treated with placebo. These findings suggest that apigenin has important chemopreventive properties for those breast cancers that develop in response to progestins. Cancer Prev Res; 4(8); 1316–24. Ó2011 AACR. Introduction however, overwhelming evidence shows that progestins stimulate proliferation of normal and neoplastic breast cells Recent clinical trials and studies show an increased risk in various species, including humans (5–8). of breast cancer in postmenopausal women undergoing A number of mechanisms have been implicated in the hormone replacement therapy (HRT) that consists of both progestin-induced increase in breast cancer risk observed estrogen and progestin (EþP) compared with women taking in women undergoing HRT, including induction of estrogen alone or placebo (1–3). Furthermore, women on a angiogenic growth factors such as vascular endothelial regimen of EþP are more at risk of metastasis and death than growth factor (VEGF) (9, 10), which renders the micro- those taking estrogen alone (4). Progestins are prescribed in environment conducive to tumor development and pro- HRT regimens to counter the unopposed proliferative effects gression. VEGF is considered one of the most important of estrogen on the uterus that could lead to uterine cancer; growth factors and its effects have been reported to be vital to the angiogenesis that is integral to the growth and metastasis of tumors (11), including those that arise in Authors' Affiliations: 1Department of Biomedical Sciences and Dalton response to progestins (7). Recently, other mechanisms 2 3 Cardiovascular Research Center, Department of Pathology, and Agri- have also been proposed to explain progestin-dependent culture Experiment Station, University of Missouri, Columbia, Missouri breast tumor development and progression. For example, Corresponding Author: Salman M. Hyder, Dalton Cardiovascular Research Center, University of Missouri, 134 Research Park Drive, Colum- in animal models, RANK-L has also been associated with bia, MO 65211. Phone: 573-882-1266; Fax: 573–884-4232; E-mail: progestin-dependent increased proliferation of breast- [email protected] cancer cells (12, 13), while it has also been reported doi: 10.1158/1940-6207.CAPR-10-0382 that medroxyprogesterone acetate (MPA), a progestin Ó2011 American Association for Cancer Research. commonly used in HRT, increased the stem-like cell 1316 Cancer Prev Res; 4(8) August 2011 Downloaded from cancerpreventionresearch.aacrjournals.org on September 30, 2021. © 2011 American Association for Cancer Research. Published OnlineFirst April 19, 2011; DOI: 10.1158/1940-6207.CAPR-10-0382 Apigenin Delays MPA-Accelerated DMBA-Induced Mammary Tumors subpopulation in mammary glands (14). Collectively, maintained according to the guidelines of the Association these observations suggest that progestins promote the for Assessment and Accreditation of Laboratory Animal growth of latent breast tumor cells by increasing their Care International under conditions of 12-hour light/dark proliferative potential and/or promote tumor develop- cycles and ad libitum access to food and water. All surgical ment through activation and transformation of dormant and experimental procedures were approved by the Institu- breast-cancer stem cells into intermediate subpopula- tional Animal Care and Use Committee of the University tions, which then differentiate into breast-cancer cells. of Missouri and were in accordance with procedures out- We have previously shown that progestins accelerate lined in the "Guide for Care and Use of Laboratory Ani- the development of 7,12-dimethylbenz(a)anthracene mals" (NIH publication 85–23). Each experiment was (DMBA)-induced mammary tumors in Sprague–Dawley carried out at least twice. rats (15–17). Whereas the molecular basis of this phe- nomenon has not been fully established, it is clear that Apigenin progestins accelerate the tumor development process by Apigenin (Indofine Chemical Company) was dissolved increasing VEGF and subsequent angiogenesis in this in a dimethyl sulfoxide (DMSO)/PBS mixture (1:4) to model (15–17). Thus, it appears that once tumor initia- produce the required concentration. Fresh apigenin was tion has occurred, progestins have the capacity to increase prepared every two days, with the remaining apigenin tumor cell proliferation, producing palpable tumors solution stored at À20C for use the following day. sooner. The progestin-accelerated DMBA-induced mam- mary tumor model is therefore a useful model in which to Experimental design identify natural "neutraceuticals" that can prevent the We followed a protocol previously established by our development of progestin-accelerated breast cancers. laboratory for progestin-acceleration of DMBA-induced Because HRT is used widely to alleviate the severe symp- mammary tumors in rats (15–17; Fig 1A). Briefly, 45- to toms of menopause, the inclusion of neutraceuticals in a 50-day-old Sprague–Dawley rats were given a single dose of drug regimen could well prove beneficial, as these com- 20 mg DMBA (Sigma) in vegetable oil by gavage (on day 0). pounds would selectively limit the proliferative effects of On day 28 post-DMBA administration, animals were progestins in the breast, protecting against the develop- anesthetized and implanted with a single 25 mg-60 day ment of frank tumors. release MPA or placebo pellet (Innovative Research) sub- Previous studies have shown that apigenin inhibits the cutaneously on the dorsal part of the neck. The dose of growth of several human cancers (18). Apigenin is a low apigenin used initially (50 mg/kg) was based on a previous molecular weight flavonoid commonly found in fruits, report (24), and was administered daily via intraperitoneal vegetables, nuts, and plant-derived beverages (19). Api- injection, beginning 21 days after the initial dose of DMBA genin exhibits low intrinsic toxicity and appears to have and continuing for 10–13 days. Control animals from the little effect on normal cells (20, 21), making it an attractive MPA implanted group and those implanted with placebo candidate for chemoprevention. Apigenin has been shown pellets only were treated with DMSO/PBS vehicle on the to be effective against several types of tumors (18), whereas same schedule. Following pellet implantation, animals its ability to act as an antiprogestin as a possible mechanism were palpated every 2 days to detect tumors. The time by which it exerts its antitumor action has not been well preceding the appearance of the first tumor (latency) studied. However, we recently showed that apigenin inhi- and tumor size, number, and location were recorded. bits progestin-dependent VEGF induction in human breast Tumor length (L) and width (W) were measured with a cancer cells in vitro (22). These findings provided a strong micrometer caliper, and tumor size was calculated using rationale for us to extend our studies to an in vivo model and the formula L/2 Â W/2 Â p (15). All animals were sacrificed examine apigenin’s ability to inhibit progestin-accelerated and the experiment terminated on day 60 and the abdom- DMBA-induced mammary tumors. Herein we provide evi- inal mammary tissue lacking tumors were collected. dence that apigenin significantly delays the appearance of In order to determine potential mechanisms by which and decreases the incidence and multiplicity of MPA-accel- apigenin could exert anticancer effects against MPA-accel- erated, DMBA-induced mammary tumors, though it
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