Endocrinology Vol. 140, No. 6 2828-2835
Copyright © 1999 by The Endocrine Society
Genetic Bases of Estrogen-Induced Pituitary Growth in an Intercross between the ACI and Copenhagen Rat Strains: Dominant Mendelian Inheritance of the ACI Phenotype1
Thomas J. Spady,
Karen L. Pennington,
Rodney D. McComb and
James D. Shull
Eppley Institute for Research in Cancer (T.J.S., K.L.P., J.D.S.),
Departments of Biochemistry and Molecular Biology (T.J.S., J.D.S.) and
Pathology and Microbiology (R.D.M., J.D.S.), University of Nebraska
Medical Center, Omaha, Nebraska 68198
Address all correspondence and requests for reprints to: Dr. James Shull, Eppley Cancer Institute, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, Nebraska 68198-6805. E-mail:
jshull{at}unmc.edu
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Abstract
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Estrogens stimulate cell proliferation in a variety of tissues and are
widely believed to be contributing factors in the etiology of certain
cancer types in humans. The molecular mechanisms through which
estrogens regulate cell proliferation are currently unknown. Estrogens
stimulate proliferation of the PRL-producing lactotroph of the rat
anterior pituitary gland and induce development of PRL-producing
pituitary tumors in several inbred rat strains. Therefore, the
lactotroph provides a well defined model for identifying the mechanisms
through which estrogens regulate cell proliferation and/or survival.
Data from our laboratory and others indicate that the relative
sensitivity to the pituitary growth-promoting actions of estrogens is
highly strain specific. This allows genetics-based approaches to be
used to address the molecular mechanisms through which estrogens
stimulate lactotroph proliferation and induce pituitary tumor
development. In the present study we have examined the ability of
diethylstilbestrol (DES) to induce pituitary growth in the genetically
related AxC-Irish (ACI) and Copenhagen (COP) strains and their derived
F1, F2, and backcross progeny. The data
presented herein indicate that the anterior pituitary gland of the ACI
strain displays approximately a 2-fold greater growth response to
administered DES than does the pituitary gland of the COP strain. The
average pituitary weight in male ACI rats was increased from 9.2
± 0.2 mg (mean ± SD) in untreated rats to 63.7
± 12.6 mg in rats treated with DES for 12 weeks, whereas in male COP
rats, DES increased pituitary weight from 12.7 ± 0.9 to 38.1
± 8.2 mg. The ACI phenotype was inherited in the F1,
F2, and backcross progeny of an ACI x COP intercross
as a dominant genetic trait, and the approximately 30 mg of additional
pituitary growth displayed by the DES-treated ACI rat, relative to that
of the treated COP rat, appeared to result from the actions of a single
locus. Moreover, in F1 progeny from an ACI x Brown
Norway intercross, the ACI phenotype was inherited as a dominant or
incompletely dominant genetic trait. These data, when compared with
findings of previous studies using the Fischer 344 rat strain, provide
the first indication that distinct genetic pathways contribute to
regulation of estrogen-induced pituitary growth and induction of
PRL-producing pituitary tumors in the ACI and F344 rat strains.
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Introduction
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ESTROGENS stimulate cell proliferation in a
variety of tissues and are widely believed to be contributing factors
to the etiology of certain types of cancer in humans. The molecular
mechanisms by which estrogens regulate cell proliferation are currently
unknown. The anterior pituitary gland of the rat provides an invaluable
model for studying estrogen action in the regulation of cell
proliferation, cell survival, and tumorigenesis. Estrogens stimulate
proliferation of the PRL-producing lactotroph and induce development of
PRL-producing pituitary tumors in males and females of several inbred
rat strains. Moreover, the relative sensitivity of the lactotroph
population to the growth-promoting and tumor-inducing actions of
estrogens is highly strain specific. Among the rat strains that develop
pituitary tumors when treated with estrogens, the Fischer 344 (F344)
strain is the most widely studied and appears to be the most sensitive.
Chronic treatment of F344 rats with either the synthetic estrogen,
diethylstilbestrol (DES), or the naturally occurring estrogen,
17ß-estradiol (E2), results in the development
of pituitary tumors after as few as 6 weeks of treatment (1, 2, 3). These
estrogen-induced pituitary tumors are markedly enlarged benign masses,
which, upon histological examination, appear highly vascularized and
often hemorrhagic and display diffuse lactotroph hyperplasia and
hypertrophy, but lack adenomatous foci (3, 4, 5). Pituitary tumor
development in the F344 rat appears to be associated with an aberrant
proliferative response of the lactotroph and perhaps other pituitary
cell populations to administered estrogen (4, 5, 6). Estrogens also appear
to exert antiapoptotic actions in the pituitary gland of the F344 rat
(4, 7). Genetics studies by Gorski and colleagues indicate that
multiple genetic loci contribute to pituitary tumor development in F344
rats treated with estrogens (8, 9, 10). In addition to F344, other rat
strains display sensitivity to the pituitary growth-promoting and
tumor-inducing actions of estrogens; these include AxC-Irish (ACI) (1, 11, 12), Wistar-Furth (13), and Copenhagen (COP) strains (14). In
contrast, the Brown Norway (BN) (9, 10), Holtzman (2, 8), and Sprague
Dawley (15) strains are insensitive to the pituitary tumor-inducing
actions of estrogens. The focus of the present study is on the ACI and
COP rat strains. Derived by Dunning and colleagues from an August
x COP cross, the ACI rat is unique among inbred rat strains in that it
displays a high susceptibility to development of mammary carcinoma when
treated with estrogens, both synthetic (16, 17) and naturally occurring
(12). In contrast, the COP strain is highly resistant to the
development of estrogen-induced mammary cancers (14, 16). Although the
genetically related ACI and COP strains display diametrically opposed
susceptibilities to estrogen-induced mammary cancers, both strains
develop PRL-producing pituitary tumors in response to chronic estrogen
treatment (1, 11, 12, 14). The purpose of the present study was to
evaluate estrogen-induced pituitary growth in the ACI and COP strains
as a quantitative genetic trait and elucidate the genetic bases for the
observed strain differences. The data presented herein indicate that
the anterior pituitary gland of the ACI strain displays an
approximately 2-fold greater growth response to administered DES than
does the pituitary gland of the COP strain, and that the ACI phenotype
behaves in progeny of an ACI x COP intercross as a dominant
genetic trait that is probably conferred through the actions of a
single locus. Comparison of these observations with previously reported
findings from studies of the F344 rat (8, 9, 10) indicate that the genetic
bases of estrogen-induced pituitary growth in the ACI rat strain differ
markedly from those in the F344 rat strain. It is concluded that there
exist in the rat species multiple genetic pathways that modulate the
manner in which the lactotroph population responds to estrogen and
impact development of PRL-producing pituitary tumors.
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Materials and Methods
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Care and treatment of animals
Male COP rats were obtained from the NCI breeding program, and
male and female ACI and male BN rats were obtained from Harlan Sprague Dawley, Inc. (Indianapolis, IN) at 6 weeks of age. These
animals were housed in a barrier animal facility under controlled
temperature, humidity, and lighting conditions. This facility is
accredited by the American Association for Accreditation of Laboratory
Animal Care and is operated in accordance with the standards outlined
in Guide for the Care and Use of Laboratory Animals (DHHS Publication
85–23). All procedures involving live animals were approved by the
institutional animal care and use committee of the University of
Nebraska Medical Center. In our animal facility, male COP rats were
mated to ACI females to produce F1 progeny.
F1 siblings were mated to produce
F2 generation, and backcross (BC) animals were
generated by mating F1 males back to their ACI
mothers. All pups were weaned at 21 days of age. Treatment of 14 ACI,
14 COP, 30 F1, 103 F2, and
19 BC rats with DES was initiated when the animals were 63 ± 2
days of age. SILASTIC brand implants (Dow Corning, Midland, MI), 2.5 cm
in length, containing 5 mg DES were prepared and surgically inserted as
described previously (14). Small populations of male ACI (n = 3),
COP (n = 3), F1 (n = 6), and
F2 (n = 6) rats remained untreated to serve as
controls. In the second intercross, BN males were mated to ACI females
to produce F1 progeny. Pups were weaned at 21
days of age. Treatment of 15 ACI, 14 BN, and 27
F1 rats with DES was initiated when the animals
were 63 ± 2 days of age. SILASTIC brand implants, 2.5 cm in
length, containing 5 mg DES were prepared and surgically inserted as
described previously (14). Small populations of male ACI (n = 7),
BN (n = 5), and F1 (n = 7) rats
remained untreated to serve as controls. Animals were allowed
continuous access to a standard laboratory chow diet (Harlan Teklad,
Madison, WI). Body weights were measured every 2 weeks throughout the
course of the experiment. The animals were killed by decapitation after
12 weeks of DES treatment. Trunk blood was collected, allowed to clot
at 4 C, and centrifuged at 1300 x g. Sera were
collected and stored at -80 C. Pituitary glands were removed and
weighed.
RIA of PRL
PRL in trunk blood serum was quantified by double antibody RIA
using an antirat PRL monoclonal antibody, PRL standards, and methods
outlined by the supplier (Amersham, Arlington Heights,
IL). The PRL standards were calibrated by the supplier against the NIH
reference RP-2 standard. The sera were diluted where appropriate. All
samples were assayed in duplicate. Inter- and intraassay coefficients
of variability were less than 10% and 6%, respectively.
Statistical analysis of data
Differences between means were evaluated using two-tailed
Student’s t test; P 
0.05 was considered
statistically significant. Observed phenotypic frequencies were
compared with those predicted by different genetic models using
2 analyses assuming two phenotypic classes (ACI and COP)
and 1 degree of freedom. A hypothesized genetic model was accepted if
2 analysis indicated P = 0.05 or
greater.
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Results
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Genetic control of estrogen-induced pituitary growth in an ACI
x COP intercross
Anterior pituitary weight correlates with cell number and DNA
content per gland and is, therefore, widely used as a surrogate
indicator of a cellular growth response to estrogen (2, 3, 4, 5). DES,
administered for 12 weeks from sc SILASTIC brand implants, induced
pituitary tumor development in both the ACI and COP rat strains as well
as in their derived F1, F2,
and BC progeny (Figs. 1
and 2). However, the ACI strain displayed an
approximately 2-fold greater pituitary growth response to DES than the
COP strain, and the ACI phenotype was conferred upon the derived
progeny as a dominant genetic trait. Average pituitary weight in male
ACI rats was increased 6.9-fold in response to 12 weeks of DES
treatment, from 9.2 ± 0.2 mg (mean ± SD) in
untreated rats to 63.7 ± 12.6 mg in DES-treated rats. In male COP
rats, DES increased pituitary weight 3-fold, from 12.7 ± 0.9 to
38.1 ± 8.2 mg. The difference in mean pituitary weight displayed
by the ACI and COP populations after DES treatment was highly
significant (P = 3.3 x 10-6). In
F1 progeny resulting from a cross between ACI
females and COP males, DES increased pituitary weight 5.8-fold, from
10.2 ± 1.2 to 58.8 ± 7.4 mg. The mean pituitary weight
observed in the DES-treated F1 population was
indistinguishable from that in the treated ACI population
(P = 0.20), but was significantly greater than that in
the treated COP population (P = 8.1 x
10-8). In the F2 population, DES
increased the mean pituitary weight 6.0-fold, from 10.1 ± 1.0 to
60.9 ± 23.9 mg. The large SD in the treated
F2 population reflected the presence of both the
ACI and COP phenotypes within this genetically heterogeneous population
of animals. (Figs. 1 and 2). Using methods developed by Wright (18), we
estimated that 84% of the total phenotypic variance in the DES-treated
F2 population was genetically conferred, whereas
the remaining 16% was due to environmental factors. Pituitary weights
in a population of DES-treated male BC progeny averaged 68.2 ±
12.5 mg, which is equivalent to that observed in the treated ACI
population (P = 0.34) but greater than that observed in
the treated COP population (P = 4.4 x
10-9).
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Figure 1. DES induces pituitary tumor development in male
ACI and COP rats and their derived F1, F2, and
BC progeny. DES treatment was initiated when the animals were 9 weeks
of age. After 12 weeks of DES treatment, the animals were killed, and
pituitary glands were removed and weighed. Data bars
represent the mean (±SD) pituitary wet weight of untreated
male ACI (n = 3), COP (n = 3), F1 (n = 6),
and F2 (n = 6) as well as DES-treated male ACI (n
= 14), COP (n = 14), F1 (n = 30), F2
(n = 103), and BC (n = 19) animals.
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Figure 2. Distribution of pituitary weights in
DES-treated progeny of the ACI x COP intercross. The frequency
distribution of pituitary weights in DES-treated male ACI, COP, F1, F2,
and BC populations are illustrated. The methods used and the number of
animals in each experimental group are described in Fig. 1 .
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To equalize variances among the populations and facilitate the
phenotypic characterization of individuals within the
F1, F2, and BC populations,
the data for pituitary weight were log transformed (19) (Fig. 3). After transformation, the
quantitative difference between the pituitary growth response of the
ACI strain and that of the COP strain remained apparent
(P = 3.7 x 10-7). Moreover, the
distribution of pituitary weights within the F1
and BC populations closely resembled that in the ACI strain
(F1 vs. ACI, P =
0.2268; BC vs. ACI, P = 0.3011), but not
that in the COP strain (F1 vs. COP,
P = 1.0 x 10-6; BC vs.
COP, P = 1.0 x 10-8). Each
individual in the F1, F2,
and BC populations was defined as being of the ACI phenotype when its
pituitary weight was greater than or equal to the mean pituitary weight
displayed by the DES-treated ACI population minus 1 SD
(
1.72 log units; 51.1 mg). An individual was classified as COP in
phenotype when its pituitary weight was less than 1 SD
greater than that displayed by the DES-treated COP population (1.66
log units; 46.3 mg). Using these criteria, 80% (24 of 30), 61% (63 of
103), and 100% (19 of 19) of the DES-treated F1,
F2, and BC populations, respectively, were
classified as ACI in phenotype; 3% (1 of 30), 25% (26 of 103), and
0% of the F1, F2, and BC
populations were classified as COP in phenotype, and 17% (5 of 30),
14% (14 of 103), and 0% of the F1,
F2, and BC populations had a pituitary weight
intermediate between those observed in the ACI and COP populations and
consequently were not classified as being either ACI or COP in
phenotype (Table 1).
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Figure 3. Distribution of log10-transformed
pituitary weights in progeny of the ACI x COP intercross. The
frequency distribution of log10-transformed pituitary
weights in untreated and DES-treated ACI, COP, F1,
F2, and BC populations is illustrated. Striped
bars represent untreated control animals, and gray
shaded bars represent animals treated with DES for 12 weeks.
The methods used and the number of animals in each experimental group
are described in Fig. 1.
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Table 1. Relatedness of observed phenotypes to those
predicted by a model in which the ACI allele of a single gene acts in a
dominant manner to confer the ACI phenotype
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Circulating PRL as an indicator of estrogen-induced pituitary
mass
DES increased circulating PRL to a greater extent in ACI males
than in COP males (P = 4.0 x 10-4),
probably reflecting the differing pituitary weights and absolute
lactotroph numbers displayed by these strains (Fig. 4). Circulating PRL levels in the
DES-treated F1 and BC populations did not differ
significantly from those in the treated ACI population
(P = 0.064 and 0.798, respectively), but did differ
significantly from those in treated COP population (P =
1.5 x 10-3 and 1.0 x 10-4,
respectively). Like pituitary weights, PRL levels in the
F2 population reflected the genetic variation
within this population. The positive correlation (correlation
coefficient = 0.882) between pituitary weight and circulating PRL
across the different DES-treated populations is illustrated in Fig. 5. This correlation indicates that
circulating PRL provides an accurate surrogate indicator of
estrogen-induced pituitary mass.
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Figure 4. DES induces hyperprolactinemia in male ACI and COP
rats and their derived F1, F2, and BC progeny.
Animals were treated as described in Materials and
Methods. At death, trunk blood serum was collected, and
circulating PRL was assayed. Data bars represent the
mean (±SEM) levels of circulating PRL from untreated
control and DES-treated male ACI, COP, F1, F2,
and BC rats. Mean PRL values of untreated controls are indicated
above the appropriate bars.
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Figure 5. Serum PRL levels positively correlate with
pituitary mass in DES-treated rats. The following scatterplot
represents pituitary wet weights (milligrams) plotted on the
x-axis vs. serum PRL values (nanograms
per ml) plotted on the y-axis of DES-treated male rat of
both parental ACI and COP strains, and the F1,
F2, and BC populations. Each data point
represents an individual animal. The following symbols were used to
represent the parental strains and derived progeny: filled
circle, ACI; open circle, COP; filled
arrowhead, F1; open arrowhead,
F2; filled square, BC.
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Genetic models of estrogen-induced pituitary growth
The observed distributions of pituitary mass in the DES-treated
F1, F2 and BC progeny from
the ACI x COP cross are most consistent with a genetic model in
which the ACI allele of a single locus acts in a dominant manner to
confer approximately 30 mg of additional pituitary growth in the
DES-treated ACI rat relative to that observed in the treated COP rat.
This 30 mg of pituitary growth represents approximately 50% of the
total growth response of the ACI pituitary gland to DES. This model
predicts that 100% of the DES-treated F1 and BC
populations should display the ACI phenotype, whereas the ACI and COP
phenotypes in the DES-treated F2 population
should occur at a ratio of 75:25. The observed data, illustrated in
Figs. 2 and 3 and summarized in Table 1, closely fit this single gene
model. We refer to the putative locus that confers this 30-mg growth
response upon the pituitary gland of the ACI rat and its progeny as
Ept1 (estrogen-induced pituitary tumor 1). Single gene
models in which the ACI allele of Ept1 acts in either a
recessive or an incompletely dominant manner were not consistent with
the observed data.
More complex genetic models were also evaluated. A model in which ACI
alleles of either of two independently segregating and dominantly
acting loci confer the additional 30 mg of pituitary growth response to
DES observed in the ACI strain predicts that 100%, 94%, and 100% of
the DES-treated F1, F2, and
BC populations would display the ACI phenotype. The observed frequency
of ACI and COP phenotypes in the F2 population
differs significantly (2 = 67.73; P <
0.0001) from that predicted by this model. A second two-gene model, in
which ACI alleles of two independently segregating loci act in concert
to confer the additional 30-mg pituitary growth response to DES,
predicts that all of the F1 and BC progeny would
display the ACI phenotype, whereas the F2
population would display the ACI and COP phenotypes at a ratio of
56:44. The observed phenotypic frequencies in F2
population also differ significantly (2 = 8.0;
P = 0.005) from those predicted by this second two-gene
model. Although the observed data do not fit this model on first
inspection, if all of the F2 animals of
unclassified phenotype were to be included in the COP phenotype, then
this two-gene model would approximate the observed data. Therefore, we
do not exclude the possibility that two, dominantly acting loci may act
in concert to confer the 30 mg of additional pituitary growth response
observed in DES-treated ACI rats. As the complexity of the examined
models was increased to three or more loci, the observed data
increasingly departed from the data predicted by each of the
models.
Genetic control of estrogen-induced pituitary growth in an ACI
x BN intercross
To allow a direct comparison of the genetic bases of
estrogen-induced pituitary growth in the ACI rat with those of the
previously characterized F344 strain (9, 10), we have also examined the
ability of DES to induce pituitary tumor development in
F1 progeny derived from a cross between the ACI
and BN strains. Average pituitary weight in male ACI rats was increased
9-fold, from 9.7 ± 0.8 to 88.9 ± 21.2 mg, in response to 12
weeks of DES treatment (Fig. 6). In
contrast, in male BN rats, DES increased pituitary weight only
1.8-fold, from 7.3 ± 0.3 to 13.2 ± 1.5 mg. In the male
F1 progeny, DES increased pituitary weight
6.4-fold, from 9.4 ± 1.5 to 61.7 ± 6.1 mg, indicating that
the ACI phenotype in this intercross is inherited as a dominant or
incompletely dominant trait.
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Figure 6. Genetic control of estrogen-induced pituitary
growth in an ACI x BN intercross. Methods are described in Fig. 1. Data bars represent the mean (±SD)
pituitary wet weight of untreated male ACI (n = 7), BN (n =
5), and F1 (n = 7) as well as DES-treated male ACI
(n = 15), BN (n = 14), and F1 (n = 27)
animals.
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Discussion
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We are using a genetics-based approach toward identification and
characterization of genes that confer or modulate the growth
response of the rat anterior pituitary gland to estrogens to gain an
understanding of the molecular mechanisms through which estrogens
regulate cell proliferation and survival. The data presented herein
indicate that male rats of both the ACI and COP strains develop
PRL-producing pituitary tumors in response to 12 weeks of DES treatment
and that the pituitary growth response of the male ACI rat is
approximately twice that of the male COP rat. Also presented are data
that strongly suggest that the approximately 30 mg of additional
pituitary growth displayed by the DES-treated ACI rat relative to that
of the DES-treated COP rat is conferred in a simple Mendelian manner
through the actions of the dominantly acting ACI allele of a single
locus, Ept1. Interestingly, the approximately 25 mg of
DES-induced pituitary growth in the ACI rat that is not attributable to
Ept1 is approximately equivalent to the entire pituitary
growth response displayed by the DES-treated COP rat. Because the ACI
and COP strains are genetically related, we hypothesize that the 25-mg
pituitary growth response of the ACI rat not attributable to
Ept1 and the entire 25-mg pituitary growth response of the
COP strain are conferred by the same locus (or loci). If the locus that
confers the 25 mg of Ept1-independent pituitary growth of
the ACI strain was to differ from the locus that confers the 25-mg
pituitary growth response of the COP strain, then it would be expected
that the two loci would segregate independently, giving rise to a
fraction of the F2 population that would display
no pituitary growth response to administered estrogen. The observation
that virtually all of the DES-treated F2 progeny
displayed the ACI or COP phenotypes, whereas none failed to develop a
pituitary tumor in response to DES, lends support to the hypothesis
that a common genetic etiology underlies the 25 mg of
Ept1-independent pituitary growth in the ACI strain and the
entire 25-mg pituitary growth response in the COP strain.
Comparison of the data presented herein with data from previous genetic
studies in which the F344 strain was crossed to the outbred Holtzman
(8) or inbred BN (9, 10) strains reveals that the genetic etiology of
estrogen-induced pituitary tumor development in the ACI rat strain is
distinct from that in the F344 strain. In neither of these previous
genetic studies was the F344 phenotype observed to be inherited as a
dominant trait. In the F344 x Holtzman intercross examined by
Wiklund et al. (8), average pituitary weights of male F344,
Holtzman, and F1 rats treated with DES for 8
weeks averaged 47, 13, and 17 mg, respectively, whereas pituitary
weights of DES-treated female F344, Holtzman, and
F1 rats averaged 88, 12, and 23 mg, respectively.
These data clearly indicate that the F344 phenotype of pituitary
growth response to estrogens is not a dominantly inherited trait. The
researchers proposed a genetic model involving at least three
independently segregating loci acting in an additive manner to confer
the F344 phenotype of pituitary growth. In the F344 x BN
intercross reported by Wendell et al. (9), pituitary weights
of female F344, BN, and F1 rats treated with DES
for 10 weeks averaged 109, 9, and 26 mg, respectively. Linkage studies
by Wendell and Gorski (10) indicate the existence of five distinct
genetic loci, located on rat chromosomes 2 (two loci), 3, 5, and 9,
that together confer approximately 55% of the pituitary growth
response of the F344 rat to DES. None of these loci appeared to confer
more than 17% of the total growth response, and only one, estimated to
confer 9% of the total growth response, appeared to act in a dominant
manner in the F344 x BN intercross. In contrast, the data
presented herein suggest that a single putative locus, Ept1,
confers 100% of the total phenotypic variance observed in the
F2 population derived from the ACI x COP
intercross. The approximately 30 mg of pituitary growth conferred by
Ept1 corresponds to approximately 50% of the total
pituitary growth response of the male ACI rat to DES. The amount of
pituitary growth conferred by Ept1 is far greater than that
conferred by the most potent of the genetic loci mapped by Wendell and
Gorski. Moreover, preliminary data from our laboratory indicate that
the genetic loci determined by Wendell and Gorski to confer the
pituitary growth response of the F344 rat to estrogen do not modulate
estrogen-stimulated pituitary growth in the ACI rat. Taken together,
these data clearly indicate that the genetic etiology of
estrogen-induced pituitary growth in the ACI rat strain is distinct
from that in the F344 strain.
PRL-producing pituitary tumors are common in humans (20, 21, 22).
Although estrogens have been implicated in the etiology of these tumors
(23, 24, 25, 26), the genetic events leading to the development of
PRL-producing pituitary tumors in humans are not well defined (27). It
is probable that identification of loci that confer regulation by
estrogen of cell proliferation and survival upon the lactotroph
population of the rat anterior pituitary gland will provide information
relevant to the etiology of human PRL-producing pituitary tumors and
perhaps other estrogen-dependent neoplasms as well.
In summary, the data presented herein strongly suggest that the ACI
allele of a putative locus, Ept1, acts in a dominant manner
to confer approximately 30 mg of additional DES-induced pituitary
growth in the male ACI rat relative to that observed in the male COP
rat. This 30 mg of induced pituitary growth represents more than 50%
of the total growth response of the ACI pituitary gland to administered
DES. Although estrogen-induced pituitary tumors in the ACI and F344 rat
strains are similar morphologically, histologically, and biochemically,
the genetic etiologies of estrogen-induced pituitary tumor development
in these strains appear distinct. We are currently mapping within the
rat genome the locations of Ept1 as a first step toward its
cloning and characterization. Knowledge pertaining to the function of
this locus and other loci that contribute to pituitary growth and
pituitary tumor development will enhance our understanding of the
molecular mechanisms through which estrogens regulate cell
proliferation and/or survival.
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Acknowledgments
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We thank David Heard, Connie Thomas, Dondi Holland, and John
Schoeman and for their invaluable assistance in the care of the
animals.
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Footnotes
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1 This work was supported by NIH Grants CA-68529 and CA-77876 (to
J.D.S.), Cancer Center Support Grant CA-36727 to the University of
Nebraska Medical Center/Eppley Cancer Center, and a Bukey
Presidential Fellowship from the University of Nebraska (to
T.J.S.). 
Received October 7, 1998.
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References
|
|---|
-
Segaloff A, Dunning WF 1945 The effect of
strain, estrogen, and dosage on the reaction of the rat’s pituitary
and adrenal to estrogenic stimulation. Endocrinology 36:238–240
-
Wiklund J, Wertz N, Gorski J 1981 A comparison of
estrogen effects on uterine and pituitary growth and prolactin
synthesis in F344 and Holtzman rats. Endocrinology 109:1700–1707[Medline]
-
Lloyd RV 1983 Estrogen-induced hyperplasia and
neoplasia in the rat anterior pituitary gland. Am J Pathol 113:198–206[Abstract]
-
Spady TJ, Lemus-Wilson AM, Pennington KL, Blackwood DJ,
Paschall TM, Birt DF, McComb RD, Shull JD 1998 Dietary energy
restriction abolishes development of prolactin producing pituitary
tumors in Fischer 344 rats treated with 17ß-estradiol. Mol Carcinog 23:86–95[CrossRef][Medline]
-
Shull JD, Birt DF, McComb RD, Spady TJ, Pennington KL,
Shaw-Bruha CM 1998 Estrogen induction of prolactin producing
pituitary tumors in the Fischer 344 rat: modulation by dietary energy,
but not protein, consumption. Mol Carcinog 23:96–105[CrossRef][Medline]
-
Wiklund JA, Gorski J 1982 Genetic differences in
estrogen-induced deoxyribonucleic acid synthesis in the rat pituitary:
correlations with pituitary tumor susceptibility. Endocrinology 111:1140–1149[Abstract]
-
Drewett N, Jacobi JM, Willgoss DA, Lloyd HM 1993 Apoptosis in the anterior pituitary gland of the rat: studies with
estrogen and bromocriptine. Neuroendocrinology 57:89–95[Medline]
-
Wiklund J, Rutledge J, Gorski J 1981 A genetic
model for the inheritance of pituitary tumor susceptibility in F344
rats. Endocrinology 109:1708–1714[Abstract]
-
Wendell DL, Herman A, Gorski J 1996 Genetic
separation of tumor growth and hemorrhagic phenotypes in an
estrogen-induced tumor. Proc Natl Acad Sci USA 93:8112–8116[Abstract/Free Full Text]
-
Wendell DL, Gorski J 1997 Quantitative trait loci
for estrogen-dependent pituitary tumor growth in the rat. Mamm Genome 8:823–829[CrossRef][Medline]
-
Holtzman S, Stone JP, Shellabarger CJ 1979 Influence of diethylstilbestrol treatment on prolactin cells of female
ACI and Sprague-Dawley rats. Cancer Res 39:779–784[Abstract/Free Full Text]
-
Shull JD, Spady TJ, Snyder MC, Johansson SL, Pennington
KL 1997 Ovary intact, but not ovariectomized female ACI rats
treated with 17ß-estradiol rapidly develop mammary carcinoma.
Carcinogenesis 18:1595–1601[Abstract/Free Full Text]
-
Lloyd RV, Coleman K, Fields K, Nath V 1987 Analysis
of prolactin and growth hormone production in hyperplastic and
neoplastic rat pituitary tissues by the hemolytic plaque assay. Cancer
Res 47:1087–1092[Abstract/Free Full Text]
-
Spady TJ, Harvell DME, Snyder MC, Pennington KL, McComb
RD, Shull JD 1998 Estrogen-induced tumorigenesis in the Copenhagen
rat: disparate susceptibilities to development of prolactin-producing
pituitary tumors and mammary carcinomas. Cancer Lett 124:95–103[CrossRef][Medline]
-
Stone JP, Holtzman S, Shellabarger CJ 1979 Neoplastic responses and correlated plasma prolactin levels in
diethylstilbestrol-treated ACI and Sprague-Dawley rats. Cancer Res 39:773–778[Abstract/Free Full Text]
-
Dunning WF, Curtis MR, Segaloff A 1947 Strain
differences in response to diethylstilbestrol and the induction of
mammary gland and bladder cancer in the rat. Cancer Res 7:511–521[Free Full Text]
-
Shellabarger CJ, Stone JP, Holtzman S 1976 Synergism between neutron radiation and diethlystilbestrol in the
production of mammary adenocarcinomas in the rat. Cancer Res 36:1019–1022[Abstract/Free Full Text]
-
Wright S 1968 The genetics of quantitative
variability. In: Evolution and the Genetics of Populations.
Genetics and Biometrical Foundations. University of Chicago Press,
Chicago, vol 1: 373–420
-
Kruglyak L, Lander ES 1995 A nonparametric approach
for mapping quantitative trait loci. Genetics 139:1421–1428[Abstract]
-
Burrow GN, Wortzman G, Rewcastle NB, Holgate RC, Kovacs
K 1981 Microadenomas of the pituitary and abnormal sellar
tomograms in an unselected autopsy series. N Engl J Med 304:156–158[Medline]
-
Annegers JF, Coulam CB, Laws Jr ER 1982 Pituitary
tumors. In: Givens JR (ed) Hormone-Secreting Pituitary Tumors.
Year Book Medical Publishers, Inc., pp 393–403
-
Molitch ME 1993 Incidental pituitary adenomas.
Am J Med Sci 306:262–264[Medline]
-
Baron SH, Sowers JR, Feinberg M 1983 Prolactinoma
in a man following industrial exposure to estrogens. West J Med 138:720–722[Medline]
-
Gooren LJG, Assies J, Asscheman H, de Slegte R, van
Kessel H 1988 Estrogen-induced prolactinoma in a man. J Clin
Endocrinol Metab 66:444–446[Abstract]
-
Panteon E, Loumaye E, Maes M, Malvaux P 1988 Occurrence of prolactinoma after estrogen treatment in a girl with
constitutional tall stature. J Pediatr 113:337–339[CrossRef][Medline]
-
Kovacs K, Stefaneanu L, Ezzat S, Smyth HS 1994 Prolactin-producing pituitary adenoma in a male-to-female transsexual
patient with protracted estrogen administration: a morphologic study.
Arch Pathol Lab Med 118:562–565[Medline]
-
Shimon I, Melmed S 1997 Genetic basis of endocrine
disease: pituitary tumor pathogenesis. J Clin Endocrinol Metab 82:1675–1681[Free Full Text]
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Abstract
Introduction
