Inhibitory Action of Aminoglutethimide on DMBA-Induced Mammary Carcinogenesis

Ar, Rao; Mg, Das; Das, Priti

doi:10.1159/000226013

Cited by 3 publications

(2 citation statements)

References 4 publications

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“…Transgenic mice that overexpress int-5/aromatase under the control of MMTV enhancer/promoter have mammary tissue predisposed to preneoplastic changes (Tekmal et al 1996). Aromatase inhibitors are successful in preventing mammary tumors in experimental animals (Rao et al 1985, Moon et al 1994, Gunson et al 1995, Grubbs et al 1996.…”

Section: Introductionmentioning

confidence: 99%

Aromatase and breast cancer susceptibility.

Probst‐Hensch¹,

Ingles²,

Diep³

et al. 1999

Endocrine-Related Cancer

139

101

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Based on experimental and epidemiological evidence it is hypothesized that estrogen increases breast cancer risk by increasing mitotic activity in breast epithelial cells. Aromatase is crucial to the biosynthesis of estrogens and may therefore play a role in breast cancer development. Supporting data for an etiological role of aromatase in breast tumor biology are several-fold. First, the association between weight and postmenopausal breast cancer risk may be mediated by aromatase. Secondly, a pilot study found a higher aromatase expression in normal breast adipose tissue from breast cancer cases as opposed to healthy women. Thirdly, experimental data in animals suggest that aromatase activity predisposes mammary tissue to preneoplastic and neoplastic changes. In a multiethnic cohort study conducted in Los Angeles and on Hawaii we investigated (i) whether the plasma estrone to androstenedione (E1/A) ratio in different ethnic groups was associated with ethnic differences in breast cancer incidence, and (ii) whether genetic variation in the CYP19 gene encoding the P450 aromatase protein was associated with breast cancer risk. The age-and weight-adjusted ethnic specific E1/A ratios ×100 among women without oophorectomy were 7.92 in African-Americans, 8.22 in Japanese, 10.73 in Latinas and 9.29 in non-Latina Whites (P=0.09). The high E1/A ratio in Latina women was not associated with a high breast cancer incidence; in fact Latina women had the lowest breast cancer incidence in the cohort observed so far. We found no consistent association of an intronic (TTTA) n repeat polymorphism with breast cancer risk in different ethnic groups. This polymorphism was not associated with differences in the plasma E1/A ratio in a way that would predict its functional relevance. We describe a newly identified TTC deletion in intron 5 of the CYP19 gene that is associated with the (TTTA) n repeat polymorphism. Neither this polymorphism, nor a polymorphism at codon 264 in exon VII of the CYP19 gene, was associated with breast cancer. We did not identify any genetic variation in exon VIII in 54 African-American subjects. We identified rare genetic variants of unknown functional relevance in the promoter I.4 of the CYP19 gene in 3 out of 24 Latina women. Further investigation into the role of aromatase in breast cancer etiology is important, given that the Endocrine-Related Cancer (1999) 6 165-173 potential use of aromatase inhibitors as breast cancer chemopreventives depends on these results.

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Section: Introductionmentioning

confidence: 99%

Aromatase and breast cancer susceptibility.

Probst‐Hensch¹,

Ingles²,

Diep³

et al. 1999

Endocrine-Related Cancer

139

101

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“…When AG was administered to intact rats during the induction and development phases of DMBA-induced mammary carcinogenesis, there was a decrease in the number of tumor-bearing animals as well as in the number of tumors per rat [34], thus suggesting an action of AG at the ovarian level. The present data obtained in OVX animals indicate for the first time that AG can also inhibit aromatase activity in peripheral tissues.…”

Section: Discussionmentioning

confidence: 99%

Androstenedione and androst-5-ene-3β,17β-diol stimulate DMBA-induced rat mammary tumors — role of aromatase

Dauvois

Labrie

1989

Breast Cancer Res Tr

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The effect of the adrenal steroids androst-5-ene-3 beta,17 beta-diol (delta 5-diol) and androstenedione (delta 4-dione) was studied on the growth of mammary carcinoma induced in the rat by dimethylbenz[a]anthracene (DMBA). The plasma levels of the two steroids were maintained at values within the range of those found in the circulation of post-menopausal women by constant release from osmotic pumps in ovariectomized animals. delta 5-diol and delta 4-dione, at the daily release rate of 500 micrograms, led to plasma levels of 1.26 +/- 0.19 and 1.72 +/- 0.75 ng/ml, respectively. At these physiologically relevant plasma concentrations, both delta 5-diol and delta 4-dione caused a marked stimulation of tumor growth while having minimal or no effect on uterine weight or on plasma prolactin and LH levels. Concomitant treatment with the aromatase inhibitor aminoglutethimide completely blocked the stimulatory effect of delta 4-dione released from silastic implants on tumor growth, while simultaneous administration of the antiandrogen flutamide had no significant effect. On the other hand, when aminoglutethimide was administered with delta 5-diol, the stimulatory effect of the adrenal steroid on tumor growth was not affected. Such data indicate that, under the present experimental conditions, transformation of delta 4-dione into androgens plays a minor role, the predominant effect of the adrenal steroid being stimulation of tumor growth through conversion into estrogens, while delta 5-diol exerts a direct estrogenic effect independent from aromatase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

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1988

Environmental Carcinogenesis Reviews

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Inhibitory Action of Aminoglutethimide on DMBA-Induced Mammary Carcinogenesis

Cited by 3 publications

References 4 publications

Aromatase and breast cancer susceptibility.

Aromatase and breast cancer susceptibility.

Androstenedione and androst-5-ene-3β,17β-diol stimulate DMBA-induced rat mammary tumors — role of aromatase

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