EXTINCTION OF EXPERIMENTAL MAMMARY CANCER, I. ESTRADIOL-17β AND PROGESTERONE

Huggins, Charles; Moon, Richard C.; Morii, Sotokichi

doi:10.1073/pnas.48.3.379

Cited by 166 publications

(70 citation statements)

References 5 publications

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“…The data reported in this study show that the natural hormone progesterone accelerates the development of DMBAinduced mammary tumors, confirming earlier reports in the literature (28,29,38). In this study, progesterone was found to increase the incidence and size of tumors when compared with the placebo control group; however, like the low-dose MPA results, it did not change the latency period compared with controls.…”

Section: Discussionsupporting

confidence: 91%

Natural and Synthetic Progestins Accelerate 7,12-Dimethylbenz[a]Anthracene-Initiated Mammary Tumors and Increase Angiogenesis in Sprague-Dawley Rats

Benakanakere

Besch‐Williford

Schnell

et al. 2006

Clinical Cancer Research

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Purpose: Synthetic progestins are widely used therapeutically; however, there is controversy regarding their proliferative effects. We used a rat 7,12-dimethylbenz [a]anthracene (DMBA)î nduced mammary tumor model to test the hypothesis that progestins increase angiogenesis and as a result decrease the latency period and increase the multiplicity of mammary tumors. Experimental Design: Medroxyprogesterone acetate (MPA) pellets were implanted 2, 4, or 6 weeks after DMBA exposure; RU-486 was given 3 days before MPA. Experiments were concluded 70 days after DMBA administration. Results: MPA exposure 4 or 6 weeks after DMBA reduced the latency period for appearance of tumors in a dose-dependent manner and increased tumor incidence. Administration of MPA 2 weeks after DMBA administration reduced tumor incidence and was protective. Progesterone did not reduce the latency period but significantly increased tumor incidence. RU-486 delayed the latency period and decreased tumor incidence in animals exposed to MPA at 4 weeks after DMBA treatment, indicating that the progesterone receptor may be partially responsible for transmission of proliferative signals. RU-486 also delayed the latency period but failed to reduce overall tumor incidence when animals were exposed to MPA at 6 weeks after DMBA treatment, indicating that other factors may also control MPA-induced acceleration.Whereas MPA-accelerated tumors were both intraductal and tubular, progesterone-accelerated and/or DMBA-induced tumors were tubular. Progestin treatment increased vascular endothelial growth factor expression within tumors in a ligand-and cell type^dependent manner and increased angiogenesis in correlation with vascular endothelial growth factor expression. No mammary tumors or progesterone receptor were detected in DMBA-treated ovariectomized rats regardless of progestin administration. Conclusions: We propose that progestins can accelerate the development of mammary tumors and that antiangiogenic agents and/or the use of antiprogestins that can reduce tumor incidence might be a viable therapeutic option for treatment of progestin-accelerated tumors. The model described here is a potentially useful preclinical model for rapidly screening such compounds.Throughout their lives, women are exposed to circulating sex hormones, both natural and synthetic. These hormones are produced by the body during sexual development, ingested in the form of oral contraception, and administered to postmenopausal women (f40% of women in the United States) as hormone replacement therapy (HRT; refs.

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Section: Discussionsupporting

confidence: 91%

Natural and Synthetic Progestins Accelerate 7,12-Dimethylbenz[a]Anthracene-Initiated Mammary Tumors and Increase Angiogenesis in Sprague-Dawley Rats

Benakanakere

Besch‐Williford

Schnell

et al. 2006

Clinical Cancer Research

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“…The use of hormones for inhibiting mammary carcinogenesis has been explored by several authors (Dao et al, 1960;Dao & Sutherland, 1959;Grubbs et al, 1983aGrubbs et al, ,b, 1986Huggins et al, 1961Huggins et al, , 1962McCormick & Moon, 1965Welsch, 1985). Among the hormones tested for this purpose have been treatment with oestrogen and progesterone at different doses (Grubbs et al, 1983b;McCormick et al, 1965), although hormone deprivation through ovariectomy or administration of the anti-oestrogen tamoxifen also inhibits mammary carcinogenesis (Welsch, 1985).…”

Section: Discussionmentioning

confidence: 99%

Comparative study of the influence of pregnancy and hormonal treatment on mammary carcinogenesis

Russo

Koszalka²,

Russo³

1991

Br J Cancer

108

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Summary Since it has been shown that pregnancy protects the mammary gland from chemically induced carcinogenesis, this study was designed with the dual purpose of determining whether treatment of young virgin rats with the placental hormone chorionic gonadotropin (hCG) mimics pregnancy-induced changes in the tumourigenic response of the mammary gland and also whether the effect induced by both pregnancy and hormonal treatments was transitory, or a more permanent one, exerting the same effect when the period of time between delivery or termination of treatment and exposure to the carcinogen is lengthened. Virgin Sprague-Dawley rats were utilised in two experimental protocols. For protocol I, 50 day-old rats were either mated (Group II), or started receiving a daily intraperitoneal injection of 100 IU hCG (Group III) at age 50.Age-matched untreated virgin rats were used as controls (Group I). Twenty-one days after either delivery or termination of treatment all the animals received an intragastric dose of 8 mg DMBA/100 gbw. For the second protocol, 50 day-old virgin rats were also mated (Group V) or were treated with hCG for 21 days (Group VI); the resting period between delivery or termination of treatment was lengthened to 63 days, at which time they received a dose of DMBA. Age-matched controls (Group IV) received DMBA only. Tumourigenesis was evaluated 24 weeks post-carcinogen administration in all the groups. Pregnancy and hCG followed by the 21-day resting period significantly depressed mammary carcinogenesis to 11% and 6% respectively, compared with 63% in control animals. When the resting period was prolonged to 63 days there was also a significant depression in adenocarcinoma incidence to 9% in pregnancy (Group V) and 7% in hCG treated (Group VI) animals respectively, vs 18% in control animals (Group IV) in which it was observed that tumour incidence was also reduced as a consequence of aging at the time of exposure to the carcinogen. These results clearly indicate that hCG is as efficient as pregnancy and significantly reduces mammary carcinogenesis, and that the protective effect of both pregnancy and hCG treatment is long-lasting and both are more efficient than aging in reducing mammary carcinogenesis.

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“…Progesterone and breast cancer have been linked since the concept of hormone-dependent cancers was first elaborated (1)(2)(3). The steroid hormone has been implicated in both the genesis and the extinction of experimentally induced mammary tumors (2)(3)(4)(5).…”

mentioning

confidence: 99%

The progesterone receptor gene maps to human chromosome band 11q13, the site of the mammary oncogene int-2.

Law¹,

Kao²,

Wei³

et al. 1987

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

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Progesterone is involved in the development and progression of breast cancers, and progesterone receptors (PR) are important markers of hormone dependence and disease prognosis. We have used a human PR cDNA probe, genomic DNA blotting of a series of Chinese hamster-human cell hybrids, and in situ hybridization to map the human PR gene to chromosome 11, band q13. This band also contains the human homolog of the mouse mammary tumor virus integration site, int-2, which surrounds a protooncogene thought to be involved in the development of murine mammary cancers. That these two genes share the same chromosomal location raises important questions about their possible linkage and about the relationship between the mammary-specific oncogene and the steroid hormone in the development, growth, and hormone dependence of human breast cancers.

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EXTINCTION OF EXPERIMENTAL MAMMARY CANCER, I. ESTRADIOL-17β AND PROGESTERONE

Cited by 166 publications

References 5 publications

Natural and Synthetic Progestins Accelerate 7,12-Dimethylbenz[a]Anthracene-Initiated Mammary Tumors and Increase Angiogenesis in Sprague-Dawley Rats

Natural and Synthetic Progestins Accelerate 7,12-Dimethylbenz[a]Anthracene-Initiated Mammary Tumors and Increase Angiogenesis in Sprague-Dawley Rats

Comparative study of the influence of pregnancy and hormonal treatment on mammary carcinogenesis

The progesterone receptor gene maps to human chromosome band 11q13, the site of the mammary oncogene int-2.

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