Hormonal environment in the induction of breast cancer in castrated rats using dimethylbenzanthracene: influence of the presence or absence of ovarian activity and of treatment with estradiol, tibolone, and raloxifene

Callejo, J.; Cano, Antonio; Medina, Marilyn; Villaronga, Miquel; González-Bosquet, Eduardo; Sabrià, J.; Lailla, Jose-Maria

doi:10.1097/01.gme.0000172269.32573.34

Cited by 5 publications

(5 citation statements)

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“…Similarly, raloxifene does not reduce tumor burden from DMBA-induction among Sencar mice (Wurz et al, 2005). However, raloxifene (3 mg/kg daily) to ovariectomized rats reduced tumorigenesis, compared to that observed in intact Sprague-Dawley rats (a more tumor prone rat model than Long-Evans rats) at the study endpoint of 6 months in another study using DMBA-induction (Callejo et al, 2005). In the present study, raloxifene was administered in more moderate dosing, which could account for why raloxifene did not block the effects of E 2 , and/or have its own effects, on tumorigenesis.…”

Section: Discussionmentioning

confidence: 91%

“…However, there are some inconsistencies in the reported effects of E 2 for tumor incidence and growth in rat models that need to be addressed. Low physiological E 2 levels can stimulate DMBA-induced tumor growth (Walf and Frye, 2009ab), but supraphysiological E 2 dosing can inhibit this growth (Callejo et al, 2005; Ohi and Yoshida, 1992). The different regimens of E 2 in these studies may account for these differences.…”

Section: Discussionmentioning

confidence: 99%

“…This dosing increased incidence of tumors and number of tumors formed (Walf and Frye, 2009ab). More chronic dosing, such as 5 mg/kg of estradiol valerate daily for 6 months, had an opposite effect to reduce DMBA-induced tumor growth (Callejo et al, 2005). In addition to different E 2 regimen, these studies differ in the strain of rats and DMBA dosing utilized, which may also account for some of the inconsistencies observed for modulation of tumor progression by E 2 .…”

Section: Discussionmentioning

confidence: 99%

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Raloxifene and/or estradiol decrease anxiety-like and depressive-like behavior, whereas only estradiol increases carcinogen-induced tumorigenesis and uterine proliferation among ovariectomized rats

Walf¹,

Frye²

2010

Behavioural Pharmacology

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Controversy surrounds the efficacy and safety of 17β-estradiol (E 2 )-mimetic therapies to women for treatment of menopausal symptoms. An important question is the nature of the trophic actions of E 2 -mimetics in the brain for behavioral processes versus in the periphery for beneficial effects related to osteoporosis, or unwanted proliferative effects in reproductive tissues, such as mammary glands and uterus. Of recent interest are the effects of selective estrogen receptor modulators (SERMs), which can have tissue specific actions, for these processes. In the present study, the effects was determined of E 2 alone, or co-administered with a SERM, raloxifene, for anxiety-like, depressionlike and trophic peripheral effects in ovariectomized rats that were exposed to a chemical carcinogen (7, 12-dimethylbenz(a)anthracene; DMBA), or not. Once per week, rats were administered vehicle, E 2 (0.09 mg/kg) and/or raloxifene (1 mg/kg) s.c. 44-48 hours before testing in a positive control, E 2 -dependent behavior (lordosis), depression (forced swim test), and anxiety (elevated plus maze) behavioral assays. In addition to behavioral endpoints, incidence and number of tumors, and tumor, pituitary gland, and uterine weight 14 weeks after carcinogen-exposure, and weekly hormone treatments, were analyzed. Rats administered DMBA had increased number and size of tumors, compared to vehicle treatment. E 2 +raloxifene increased the number of tumors. Administration of E 2 or E 2 +raloxifene, but not raloxifene alone, increased pituitary and uterine weight, compared to vehicle administration. E 2 or E 2 +raloxifene, but not raloxifene alone, also increased incidence of lordosis and reduced depression-like behavior in the forced swim test (i.e. decreased time spent immobile) compared to vehicle administration. However, administration of E 2 or raloxifene reduced anxiety behavior in the elevated plus maze (i.e. increased time spent on the open arms of the maze), compared to vehicle. Together these data demonstrate that E 2 and/or raloxifene can have some effects to alter behavior of ovariectomized rodents, depending upon task. As well, E 2 , with or without raloxifene, can also have clear trophic actions in peripheral tissues, such as carcinogen-induced tumors, uterus, and pituitary glands.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Raloxifene and/or estradiol decrease anxiety-like and depressive-like behavior, whereas only estradiol increases carcinogen-induced tumorigenesis and uterine proliferation among ovariectomized rats

Walf¹,

Frye²

2010

Behavioural Pharmacology

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“…Hemiovariectomized rats administered DMBA and E 2 pellets had mammary dysplasia 3 and 6 months following initiation of treatment, whereas dysplasia was only noted at 6 months following treatment with DMBA alone (Ting et al 2007). Furthermore, the effect of E 2 to increase mammary tumors following DMBA administration is not observed in animals that do not develop a mature hypothalamic-pituitary-gonadal axis (i.e., those that are castrated before puberty; Callejo et al 2005). This suggests that prior E 2 exposure is an important variable in this model.…”

Section: Discussionmentioning

confidence: 94%

Estradiol enhances sociosexual behavior and can have proliferative effects in ovariectomized rats

Walf

Frye

2008

AGE

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Although estradiol (E 2 ) may have some beneficial effects as a treatment for menopause symptoms, E 2 also has trophic effects that can increase vulnerability to some cancers, such as breast cancer. In the present study, a model to investigate the concomitant behavioral and proliferative effects of E 2 was developed. First, the effects of different duration of chronic E 2 exposure (2 vs 6 months), or no such exposure, on proliferation (tumor incidence and weight, uterine weight) in adult, ovariectomized (OVX) rats was determined. Second, the effects of different dosages of E 2 (0.03 or 0.09 mg/kg) compared to vehicle only on sexual behavior, and measures of proliferation of adult OVX rats treated with a chemical carcinogen (DMBA; 1.25, 12.50, or 25.00 mg), or inert vehicle, were investigated. Vehicle or E 2 was administered subcutaneously (SC) to OVX rats once per week for 14 weeks. Six months of continuous E 2 exposure increased tumor incidence, tumor weight, and uterine weight, compared to 2 months of E 2 or no E 2 exposure. Rats administered DMBA had increased incidence, number, and size of tumors compared to vehicle treatment, and this effect appeared to be augmented by E 2 . Compared to vehicle, E 2 increased lordosis and uterine weight. Thus, E 2 may have the unfavorable effect of increasing proliferation when administered in chronic situations. Studies investigating the action of E 2 for these effects are ongoing.

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“…Recently, in an experimental model, it has been shown that tibolone as well as raloxifene and oestradiol did not promote breast cancer in rats treated with dimethylbenzanthracene. 16 In studies with ovariectomised cynomolgus macaques, it has been reported that tibolone did not cause stimulation of the breast, as measured by an increase in breast epithelial tissue area and expression of the proliferation marker Ki-67 in breast epithelial cells. In addition, at higher doses, tibolone increased progesterone receptor expression in the breast tissue relative to controls, indicating a partial oestrogenagonist activity, but without induction of proliferation.…”

Section: Animal Studiesmentioning

confidence: 98%

Tibolone and breast cancer

Erel

Şentürk²,

Kaleli³

2006

Postgraduate Medical Journal

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Tibolone is a relatively new drug for postmenopausal women, which is structurally related to 19-nortestosterone derivatives and exhibits weak oestrogenic, progestogenic and androgenic activities. The effect of tibolone on breast tissue is still obscure. In vitro studies have shown conflicting results regarding the effects of tibolone on breast cells. On the other hand, although epidemiological studies show an increase in the risk of breast cancer among women treated with tibolone, accumulation of data obtained from radiological studies presents promising results. However, the safety of tibolone with regard to breast tissue needs to be investigated further, especially through well-designed, large-scale, randomised-controlled trials.

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Hormonal environment in the induction of breast cancer in castrated rats using dimethylbenzanthracene: influence of the presence or absence of ovarian activity and of treatment with estradiol, tibolone, and raloxifene

Abstract: In this experimental model and using the hormone treatments chosen, neither the treatments nor the absence of ovarian activity induced breast cancer.

Cited by 5 publications

References 45 publications

Raloxifene and/or estradiol decrease anxiety-like and depressive-like behavior, whereas only estradiol increases carcinogen-induced tumorigenesis and uterine proliferation among ovariectomized rats

Raloxifene and/or estradiol decrease anxiety-like and depressive-like behavior, whereas only estradiol increases carcinogen-induced tumorigenesis and uterine proliferation among ovariectomized rats

Estradiol enhances sociosexual behavior and can have proliferative effects in ovariectomized rats

Tibolone and breast cancer

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