Antagonism of Development and Growth of 7, 12-Dimethylbenz(a)anthracene-induced Rat Mammary Tumors by the Antiestrogen U 23, 469 and Effects on Estrogen and Progesterone Receptors

Ten Lin Sie Tsai, Benita S Katzenellenbogen

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Abstract

This study analyzes the effectiveness of a nonsteroidal antiestrogen, cis-(3-[p-(1, 2, 3, 4-tetrahydro-6-methoxy-2-phenyl-1-naphthyl)phenoxy]-1, 2-propanediol (U 23, 469) previously shown to be potent in antagonizing estrogen-induced uterine growth, in preventing the development of 7, 12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumors and in eliciting the regression of established tumors; the study also attempts to elucidate the mechanisms of the tumor antagonism of U 23, 469. Virgin female Sprague-Dawley rats that receive DMBA at 47 to 50 days of age and then receive U 23, 469 (250 μg s.c. in 0.15 mNaCl daily) have a greatly reduced number of mammary tumors and a markedly decreased tumor area. Treatment with U 23, 469 for increasing time periods (3, 6, or 12 weeks) beginning 2 weeks after DMBA results in a progressive decrease in tumor size and number and a progressive delay in onset of tumor appearance. U 23, 469 treatment beginning 1 week after DMBA or given prior to DMBA is even more effective. The time course of tumor regression (3 months after DMBA) by U 23, 469 or ovariectomy is similar, with 50% regression in ca. 2 weeks, and both elicit regression of almost all tumors (>90%). After ovariectomy, cytosol progesterone receptor levels are greatly diminished in tumors and uteri, while cytosol estrogen receptor (ER) levels are high; in both tissues little (ca. one-third) of ER is in the nucleus. During U 23, 469 treatment, cytosol ER content is very low in regressing tumor and uterus and over 90% of ER is in the nucleus; cytosol progesterone receptor is slightly depressed in the uterus but is at the untreated level in mammary tumor. These receptor studies suggest that the effectiveness of this antiestrogen in antagonizing mammary tumor development and growth may reside in its ability markedly to perturb the distribution of ER, maintaining over 90% of ER in the nucleus with concomitant low levels of cytoplasmic ER, a situation that may render the mammary tissue insensitive to the animal's own endogenous estrogens.

Original languageEnglish (US)
Pages (from-to)1537-1543
Number of pages7
JournalCancer Research
Volume37
Issue number5
StatePublished - May 1977

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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