Effect of ovarian hormones on the induction of 1-methyl-1-nitrosourea-induced mammary cancer

Grubbs, Clinton J.; Peckham, John; McDonough, Karen D.

doi:10.1093/carcin/4.4.495

Cited by 41 publications

(27 citation statements)

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“…Normal cells proliferate and differentiate in the presence of high levels of hormones, but cancer cells are killed. Grubbs demonstrated that treatment with high levels of estradiol and progesterone after MNU treatment was as effective as ovariectomy in preventing mammary carcinogenesis (11). He suggested that the primary action of the hormones is to cause differentiation of the preneoplastic cells.…”

Section: Discussionmentioning

confidence: 99%

“…Russo and Russo and Grubbs et al (4,7,11,12) suggested that the primary action of the hormones is to cause normal differentiation of potential target cells. The interpretation of Medina and colleagues is that hormone treatment results in persistent alterations in the intracellular pathways governing proliferation responses to carcinogens (13).…”

Section: Discussionmentioning

confidence: 99%

“…Treatments with human chorionic gonadotropins or combinations of estradiol and progesterone, either before or after treatment with chemical carcinogens, both induce lobuloalveolar differentiation and are protective (7,(9)(10)(11)(12)(13). The most accepted explanation for this induced refractoriness to mammary carcinogenesis is that either the mammary target cells for cancer induction are altered by prior hormonal treatment to a nonsusceptible state (4,13) or, in the case of hormonal treatment after carcinogen administration, the preneoplastic cells induced by the carcinogen treatment differentiate (11,12) or undergo apoptosis (14).…”

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confidence: 99%

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Hormonal prevention of breast cancer: Mimicking the protective effect of pregnancy

Guzman

Yang

Lakshmanaswamy

et al. 1999

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

192

144

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Full term pregnancy early in life is the most effective natural protection against breast cancer in women. Rats treated with chemical carcinogen are similarly protected by a previous pregnancy from mammary carcinogenesis. Proliferation and differentiation of the mammary gland does not explain this phenomenon, as shown by the relative ineffectiveness of perphenazine, a potent mitogenic and differentiating agent. Here, we show that short term treatment of nulliparous rats with pregnancy levels of estradiol 17␤ and progesterone has high efficacy in protecting them from chemical carcinogen induced mammary cancers. Because the mammary gland is exposed to the highest physiological concentrations of estradiol and progesterone during full term pregnancy, it is these elevated levels of hormones that likely induce protection from mammary cancer. Thus, it appears possible to mimic the protective effects of pregnancy against breast cancer in nulliparous rats by short term specific hormonal intervention.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Hormonal prevention of breast cancer: Mimicking the protective effect of pregnancy

Guzman

Yang

Lakshmanaswamy

et al. 1999

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

192

144

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“…Subsequently, female Sprague-Dawley rats treated with MNU were shown to develop multiple hormonally responsive mammary cancers starting within 5 weeks after carcinogen administration (11). These cancers seem to be histologically similar to ER + mammary cancers in humans (12).…”

Section: Introductionmentioning

confidence: 99%

Effects of gefitinib (Iressa) on mammary cancers: preventive studies with varied dosages, combinations with vorozole or targretin, and biomarker changes

Lubet

Szabó

Christov

et al. 2008

Molecular Cancer Therapeutics

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The ability of the epidermal growth factor receptor inhibitor gefitinib (Iressa) to prevent/treat methylnitrosourea (MNU)-induced mammary cancers and to modulate biomarkers in female Sprague-Dawley rats was examined. Rats were given a single dose of MNU (75 mg/kg body weight) at 50 days of age. In the prevention studies, continual treatment with Iressa at 10, 3, or 1 mg/kg body weight per day beginning 5 days after MNU reduced tumor multiplicity by 93%, 43%, and 20%, respectively. Treatment of rats bearing small palpable cancers with Iressa (10 mg/kg body weight per day) resulted in the complete regression of 70% of the tumors. Short-term treatment of tumor-bearing rats with Iressa caused decreases in cell proliferation and phosphorylated epidermal growth factor receptor and increases in apoptosis. To examine treatment regimens that might decrease the skin toxicity associated with Iressa, both intermittent treatments and combinations of lower doses of Iressa with other effective agents were evaluated.

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“…Short-term treatment of young adult rats (≤3 months old) with estrogen and progesterone mimics the pregnancy milieu and is highly effective in suppressing mammary carcinomas in carcinogen-exposed rats (11,14,21,22). The E/P pellet we used elevates serum 17ß-estradiol and progesterone levels 2 weeks after implantation to levels comparable to pregnancy, which then drop to control levels 8 weeks after implantation (21).…”

Section: Discussionmentioning

confidence: 99%

Biphasic effect of short-term pregnancy hormone treatment on N-methyl-N-nitrosourea-induced mammary carcinogenesis in young and old rats

Tsubura¹

2009

Mol Med Rep

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Abstract. This study examined the development of N-methyl-N-nitrosourea (MNU)-induced mammary carcinomas in young and old female Lewis rats following short-term treatment with estrogen and progesterone to mimic pregnancy. Rats exposed at 4 weeks of age to MNU were treated at 6 weeks of age (early MNU/young E/P treatment) or at 24 weeks of age (early MNU/old E/P treatment) with a 21-day slow-release pellet containing 0.5 mg 17ß-estradiol and 32.5 mg progesterone (E/P). Other rats were exposed to MNU at 22 and again at 23 weeks of age, and were treated with E/P at 24 weeks of age (late MNU/old E/P treatment). All experimental groups were compared with respective MNU-exposed age-matched E/Puntreated rats. Overt mammary carcinomas (≥1 cm in diameter) that were positive for hormone receptors were reduced in young E/P-treated rats, while hormone receptor-negative overt mammary carcinomas increased in old E/P-treated rats. The rate of development of small-sized mammary carcinoma (<1 cm in diameter) was similar in early MNU/young E/Ptreated and late MNU/old E/P-treated groups, but higher in early MNU/old E/P-treated rats compared with respective E/Puntreated rats. At the termination of the experiment, normal mammary gland architecture had not been influenced by E/P treatment, although E/P treatment of older rats caused an increase in proliferating cell nuclear antigen (PCNA) labeling of the mammary tissue. Thus, the impact of short-term E/P treatment on MNU-induced rat mammary carcinogenesis is age-dependent and shows biphasic effects; the development of hormone-dependent overt mammary carcinomas was reduced in young rats but the development of hormoneindependent overt mammary carcinomas increased in older rats. The enhanced outgrowth of hormone-independent overt mammary carcinomas by E/P treatment in old age is due to accelerated cell proliferation at the promotion/progression phase of mammary carcinogenesis. Age at short-term E/P treatment is crucial for breast cancer control.

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Effect of ovarian hormones on the induction of 1-methyl-1-nitrosourea-induced mammary cancer

Cited by 41 publications

References 0 publications

Hormonal prevention of breast cancer: Mimicking the protective effect of pregnancy

Hormonal prevention of breast cancer: Mimicking the protective effect of pregnancy

Effects of gefitinib (Iressa) on mammary cancers: preventive studies with varied dosages, combinations with vorozole or targretin, and biomarker changes

Biphasic effect of short-term pregnancy hormone treatment on N-methyl-N-nitrosourea-induced mammary carcinogenesis in young and old rats

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