The direct antitumoral effects of
gonadotropin-releasing hormone (
GnRH) analogues on
breast tumors have been surmised from clinical observations and in vitro studies. The present study aimed to determine the effects of the
GnRH agonist [D-Trp6]
GnRH (
Decapeptyl) on steps of experimental mammary
carcinogenesis, and the mechanisms, other than the chemical
castration, involved. We chose a recent model, i.e., mammary
tumors induced by wild-type A2 polyoma (Py) virus in BALB/c female nu/nu mice, which displays the following characteristics.
Tumors are mammary
adenocarcinomas similar to well differentiated
breast carcinomas.
Tumor promotion period ends 20 days after Py virus inoculation and is
estradiol dependent. The first palpable
tumors occur 60 days after Py virus inoculation, and
tumor growth is ovarian
hormone independent. The effects of
Decapeptyl treatment on
tumor induction and
tumor growth were studied in normal or ovariectomized 6-week-old nude mice inoculated with 10(7) plaque-forming units Py virus (day 0 of experiments). Normal mice and ovariectomized mice percutaneously supplemented with 0.6 micrograms
17 beta-estradiol every other day until day 30 (OvE2 mice) were treated with monthly s.c.
injections of the sustained release form of
Decapeptyl (5 mg/kg) until the end of 180-day experiments. Overall values for latency periods were included within a day 60 to day 130 time interval.
Hormone-independent outgrowth was not affected. We focused on
tumor progression before the outgrowth. Incidences on
tumor appearance kinetics account for effects at this stage.
17 beta-Estradiol repletion strongly antagonized (P less than 0.001) the slowing effect of
ovariectomy on the
tumor appearance kinetics, indicating that
tumor progression is
estradiol sensitive in its early stages. [D-Trp6]
GnRH treatment antagonized
tumor appearance profiles, inducing similar kinetics in both normal and OvE2 mice. In normal mice, the antagonism (P less than 0.01) was concomitant with significant decreases (P less than 0.05) in serum levels of
estradiol and
prolactin, which are critical
hormones for mammary
tumor development in mice, suggesting a pituitary-mediated effect. In OvE2 mice, the antagonism (P less than 0.01) occurs independently of
estradiol and
prolactin, suggesting a direct effect at the mammary cell level. Because of alterations in kinetics, this effect is exerted at the early stages of
tumor progression on Py virus-transformed, ovarian
hormone-sensitive cells in the mammary tissue. This new animal model of
breast cancer is shown to be useful in characterizing direct antitumoral effects of
GnRH analogues and studying the basic mechanisms of mammary
carcinogenesis.