CPB 697 RESEARCH SEMINAR
Julia Lucas,
Graduate Student in Anatomic Pathology
Department of Comparative Pathobiology
“Virilism In The Rat Mammary Gland Induced By The
Selective Estrogen Modulator, LY504132:
Comparison With
Other Selective Estrogen Receptor Modulators
And
Investigation Of Mechanisms Of Glandular Hyperplasia”
Thursday, March 22, 2007
VPTH 112
3:30 pm
Abstract:
Selective estrogen
receptor modulators (SERMs) are non-steroidal compounds with tissue dependent
estrogen receptor (ER) agonism or antagonism.
In previous work, female rats treated with, LY504132 (SERM), had
hyperandrogenemia and mammary gland hyperplasia and hypertrophy (virilism);
that was blocked by co-treatment with flutamide (androgen receptor
antagonist). The objective of this study
was to compare a structurally diverse group of SERMs, including LY504132 in
female rats, to provide evidence that mammary virilism is common to SERMs that
stimulate the ovary and induce excess androgen production.
Female rats treated for
30 days with one LY504132, TSE424, Tamoxifen and 117018, all ER antagonists in
the rat mammary gland, or DHT (positive control) / vehicle (negative
control). Plasma testosterone and
estradiol levels; and morphologic alterations of the mammary gland were
evaluated. Three of the compounds (LY504132, TSE424, and 117018) induced
alterations consistent with mammary virilism.
Tamoxifen treatment did not result in hyperandrogenemia or mammary
virilism indicating mammary gland virilism is not caused by ER antagonism
alone. The mammary gland changes induced
by DHT were similar to those induced by the SERMs that caused virilism;
however, ductal and alveolar structures were dilated with secretory material,
indicating the SERM lesion is not reproduced by a pure androgen and must
involve SERM modulation of other hormones or receptors either locally in the
mammary gland or systemically (pituitary).
This lead to the second study to compare the effects of LY504132 and DHT on the mammary gland over time: female rats were treated for up to 30 days and serial sacrificed at 2, 4, 14 and 30 days. Plasma testosterone and estradiol levels; morphologic alterations of the mammary gland, uterus and ovary; and androgen and estrogen receptor expression and activation were evaluated to understand of how DHT and LY504132 differ in their effect on mammary epithelium over time. Androgen receptors and genes are induced similarly by DHT and LY504132 over time; indicating the differences between DHT and SERM virilism is not attributable to the way they affect the AR. ER evaluation is in progress. Proliferation and apoptosis were evaluated in mammary tissue to understand of how DHT and LY504132 differ in their effect on the growth of mammary epithelium. There was no up regulation in proliferation between controls DHT or LY504132, but apoptosis was inhibited by LY504132, although there was no difference in the effect of DHT or LY504132 on the activity of two genes evaluated for apoptosis. Growth hormone, IGF-1, progesterone and prolactin expression and activation were evaluated in mammary tissue for evidence that DHT and LY504132 mediate their effect on mammary epithelium by other growth factors. There was no evidence that IGF1 was up-regulated by either DHT or LY504132, but other growth factors are still to complete analysis.