Parous rats regain high susceptibility to chemically induced mammary cancer after treatment with various mammotropic hormones

Thórdarson, Gudmundur; Horn, Katharine Van; Guzman, Raphaël; Nandi, Satyabrata; Talamantes, Frank

doi:10.1093/carcin/22.7.1027

Cited by 28 publications

(26 citation statements)

References 24 publications

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“…These experiments, performed in the pre-and post-treatment models, definitely demonstrate that pregnancy primarily delays progression. Along these lines, the provocative experiments by Thordarson et al (2001), that continuing the same doses of hormones for an extended period of time (20 rather than 3 weeks) results in abundant tumor development equivalent to the AMV, indicate that hormones can promote progression, if administered continuously. A similar conclusion was reached in the parous mouse using pituitary isografts as the source of hormones .…”

Section: Mechanisms Of Protection Initiation Vs Promotionmentioning

confidence: 98%

Mammary developmental fate and breast cancer risk

Medina

2005

Endocr Relat Cancer

108

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The ovarian hormones, estrogen and progesterone, play a pivotal role in normal and neoplastic development of the mammary gland. These hormones have a paradoxical role as long duration of estrogen and progesterone are associated with increased breast cancer risk, while short duration of pregnancy level doses are associated with a reduced breast cancer risk. The protective effects of estrogen and progesterone, as well as pregnancy, have been extensively studied in animal models. Recent studies have demonstrated that these hormones induce alterations in gene expression in the mammary epithelial cells which persist for a long time after the hormones are withdrawn from the host. It is postulated that hormones induce a switch in mammary developmental fate which decreases the risk of breast cancer over the lifetime of the host. Some of the possible cellular pathways persistently altered by short term hormone exposure are a decrease in growth factors and an increase in apoptosis. The expression of these genes, in turn, may be affected by alterations in genes regulating chromatin remodeling. The relative contributions of host-mediated factors and mammary cell intrinsic factors remain to be determined. The current studies have moved this research area from the biological to the molecular realm and offer the potential for directing prevention efforts at specific molecular targets.

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Section: Mechanisms Of Protection Initiation Vs Promotionmentioning

confidence: 98%

Mammary developmental fate and breast cancer risk

Medina

2005

Endocr Relat Cancer

108

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“…Furthermore, the splenocytes of parous rats have significantly higher cytotoxic activity against mammary tumor cells when compared with virgin controls (29). It has been reported that parous rats have decreased levels of mammogenic hormones, and this decrease has been attributed to the decreased incidence of mammary cancers in these animals (30,31). In our laboratory, we had shown that differentiation of the mammary gland alone was not enough to confer protection against mammary cancer (23).…”

mentioning

confidence: 95%

Short-term exposure to pregnancy levels of estrogen prevents mammary carcinogenesis

Lakshmanaswamy

Guzman

Yang

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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107

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It is well established that pregnancy early in life reduces the risk of breast cancer in women and that this effect is universal. This phenomenon of parity protection against mammary cancer is also observed in rodents. Earlier studies have demonstrated that shortterm administration of estradiol (E) in combination with progesterone mimics the protective effect of parity in rats. In this study, the lowest effective E dosage for preventing mammary cancer was determined. Rats were injected with N-methyl-N-nitrosourea at 7 weeks of age; 2 weeks later, the rats were subjected to sustained treatment with 20 g, 100 g, 200 g, or 30 mg of E in silastic capsules for 3 weeks. Treatments with 100 g, 200 g, and 30 mg of E resulted in serum levels of E equivalent to those of pregnancy and were highly effective in preventing mammary cancer. E treatment (20 g) did not result in pregnancy levels of E and was not effective in reducing the mammary cancer incidence. In another set of experiments, we determined the effect of different durations of E with or without progesterone treatments on mammary carcinogenesis. These experiments indicate that a period as short as one-third the period of gestation is sufficient to induce protection against mammary carcinogenesis. The pioneering aspect of our study in contrast to long-term estrogen exposure, which is thought to increase the risk of breast cancer, is that short-term sustained treatments with pregnancy levels of E can induce protection against frank mammary cancer. B reast cancer is the most common cancer among women worldwide. The incidence of breast cancer in the United States for the year 2000 was estimated to be Ϸ184,200 new cases (1). The epidemiological evidence provides strong support for the concept that environmental, hormonal, and genetic factors affect the risk for development of breast cancer (2-6). Among the various recognized reproductive risk factors are age at menarche, age at first pregnancy, and age at menopause, all of which seem to suggest that endogenous ovarian steroids may profoundly affect the process of carcinogenesis (3,6,7).Various studies reveal that nulliparous women have a higher risk of breast cancer compared with women who have undergone single or multiple pregnancies early in life (8-10). The protective effect of pregnancy is universal, and pregnancy is the only normal physiological condition that consistently prevents breast cancers in all ethnic backgrounds in all countries without known adverse effects (8-10). The phenomenon of parity protection against mammary carcinogenesis is also observed in rats and mice. Moon (11) demonstrated that parous rats exposed to chemical carcinogens developed fewer cancers compared with virgin rats. Earlier Marchant (12) and very recently Medina and Smith (13) have demonstrated that pregnancy provides protection against mammary carcinogenesis in mouse models. Shortterm administration with ovarian steroids [estrogens and progesterone (P)] or human chorionic gonadotropins either before or after carcinogen treatment dec...

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“…There are now data indicating that progesterone could also play a pivotal role in tumorigenesis. It was shown that progestins have a role in the initiation and/or progression of rat and mouse mammary tumors (Lydon et al, 1999;Thordarson et al, 2001;Lanari and Molinolo, 2002). However, clinical and epidemiological investigations remain controversial concerning the exact implication of progesterone in breast tumorigenesis in women, and the risk of use progestin in addition to estrogen in postmenopausal hormone replacement therapy is still being debated.…”

Section: Introductionmentioning

confidence: 99%

Progesterone prevents radiation-induced apoptosis in breast cancer cells

Varès¹,

Ory²,

Lectard³

et al. 2004

Oncogene

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Sex steroid hormones play an essential role in the control of homeostasis in the mammary gland. Although the involvement of progesterone in cellular proliferation and differentiation is well established, its exact role in the control of cell death still remains unclear. As dysregulation of the apoptotic process plays an important role in the pathogenesis of breast cancer, we investigated the regulation of apoptosis by progesterone in various breast cancer cell lines. Our results show that progesterone treatment protects against radiation-induced apoptosis. This prevention appears to be mediated by the progesterone receptor and is unrelated to p53 status. There is also no correlation with the intrinsic hormonal effect on cell proliferation, as the presence of cells in a particular phase of the cell cycle. Surprisingly, progesterone partly allows bypassing of the irradiation-induced growth arrest in G 2 /M in PgR þ cells, leading to an increase in cell proliferation after irradiation. One consequence of this effect is a higher rate of chromosome damage in these proliferating progesterone-treated cells compared to what is observed in untreated irradiated cells. We propose that progesterone, by inhibiting apoptosis and promoting the proliferation of cells with DNA damage, potentially facilitates the emergence of genetic mutations that may play a role in malignant transformation.

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Parous rats regain high susceptibility to chemically induced mammary cancer after treatment with various mammotropic hormones

Cited by 28 publications

References 24 publications

Mammary developmental fate and breast cancer risk

Mammary developmental fate and breast cancer risk

Short-term exposure to pregnancy levels of estrogen prevents mammary carcinogenesis

Progesterone prevents radiation-induced apoptosis in breast cancer cells

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