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Experimental Therapeutics, Preclinical Pharmacology |
Department of Surgery [K. Y., D. J. B., G. E.], R. H. Lurie Comprehensive Cancer Center [E-S. L., J. I. M. S., V. C. J.], and the Division of Medical Oncology [R. M. O.], Northwestern University Medical School, Chicago, Illinois 60611
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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This unique observation of a tumoricidal effect of E2 on two independent TAM-stimulated MCF-7 tumor lines raises the possibility that the clinical effectiveness of long-term TAM may not result from indefinite treatment but from the cessation of therapy at the appropriate time. A woman’s own estrogen may then produce a tumoricidal action on the supersensitized cells after TAM is cleared from the body. Additionally, these data in the laboratory also suggest that estrogen treatment of recurrent breast cancer after the failure of long-term TAM (on the presumed development of ER-positive, TAM-stimulated tumors) may result in a tumor regression that returns the breast cancer cells to estrogen responsiveness.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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1-mm3 pieces in a bath of cold RPMI
1640. Tumor pieces were then implanted with a 13-gauge trocar
into the axillary mammary fat pads of the mice. At the time of tumor
transplantation, all animals were also implanted s.c. with a silastic
capsule containing either TAM or E2, depending on
the specific experiment. For tumor harvests, animals were killed by CO2 inhalation and cervical dislocation, and tumors were removed and snap-frozen in liquid nitrogen. Frozen tumor specimens were stored at -80°C until use.
Hormone Treatments.
TAM was administered either p.o. or s.c. (via a 2-cm silastic capsule
filled with TAM), depending on the type of experiment. TAM was
administered p.o. at doses ranging from 500 to 1500 µg as a
suspension of 10% PEG 400/Tween 80 (99.5% PEG/0.5% Tween 80)
and 0.9% carboxymethyl cellulose (0.05 ml). The capsule produced blood
levels of TAM of 30–40 ng/ml (12)
.
E2 was administered s.c. via either a 0.3- or
1-cm silastic capsule filled with E2, implanted
s.c. into the animal’s back. The capsules produced serum levels of
83.8 and 379 pg/ml, respectively (13)
, and were used to
mimic post- or premenopausal levels of E2. In one
experiment, an E2 pellet (1.5 mg) from Innovative
Research of America (Toledo, OH) was used to replicate pharmacological
doses of E2. Serum levels of 1044 ng/ml were
noted (13)
. The E2 and TAM capsules
were replaced every 6–8 weeks (13)
.
Tumor Measurements.
Tumor measurements were performed weekly using Vernier calipers. Tumor
cross-sectional area was calculated using the formula: length/2 x
width/2 x 
. Mean tumor area was plotted against time in weeks
to monitor tumor growth.
SSCP.
Total RNA was prepared from tumors using the TRIzol reagent (Life
Technologies, Inc.). SSCP was performed using the methods originally
described by Orita et al. (14
, 15)
but with
minor modifications (16)
. Tumor total RNA (1 µg) was
reverse transcribed in a 20-µl reaction containing 50
mM Tris-HCl (pH 8.3), 75 mM
KCl, 3 mM MgCl2, 0.5
mM each dATP, dCTP, dGTP, and dTTP, 10
mM DTT, 3 µM
oligo(dT)12–14, 100 units of placental RNase inhibitor, and 200 units
of Moloney murine leukemia virus reverse transcriptase. The DNA
fragment containing the 351 codon was generated by PCR from 5 µl of
reverse transcription mixture using two primers,
5'-GAGACATGAGAGCTGCCAAC-3' and 5'-GGGTGCTGGACAGAAATGTG-3'. Control
amplification was carried out on 50 pg of double-stranded DNA, coding
for either a wild-type ER (HEGO) or a mutant ER (HETO), which contains
a single G-to-T point mutation at nucleotide 1559. The PCR cycles and
conditions have been described previously (9)
.
An aliquot of 32P-labeled DNA was digested with XbaI restriction endonuclease. After restriction digestion, an aliquot of cut and uncut DNA was diluted 1:4 with 0.1% SDS, 10 mM EDTA. Half of each diluted sample was mixed 1:1 with nondenaturing loading buffer (50% glycerol, 0.05% bromphenol blue, and 0.05% xylene cyanol), and the remaining half was mixed 1:1 with denaturing loading buffer (95% formamide, 20 mM EDTA, 0.05% bromphenol blue, and 0.05% xylene cyanol). The samples were electrophoresed on a 6% neutral polyacrylamide gel with 14–16 W constant power for 4 h.
Statistical Analysis.
Differences in mean tumor area between groups were measured using
ANOVA, followed by unpaired Student’s t test.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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0.4-cm2. At this point, the TAM capsule was
removed, and the animals were randomized into two groups of drug
treatment. One group was implanted with an E2 (1
cm) capsule that delivers E2 levels of 379 pg/ml
serum (13)
and the other half a TAM (2 cm) capsule (30–40
ng/ml). The serum levels of E2 and TAM were
within the ranges documented in premenopausal women (17)
and those taking TAM as adjuvant therapy (17
, 18)
. After 2
weeks, the tumors began to regress in the
E2-treated mice, and after 5 weeks, the tumors
were 0.1 cm2 in size (Fig. 1A)
. Interestingly, after 6
weeks of E2 treatment, 8 of 18 tumors started to
grow in the E2 group. We designated this line
MCF-7TAME (a newly estrogen-responsive MCF-7TAM tumor).
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. Six
weeks after stopping TAM treatment or starting treatment with
E2, the treatment groups readily displayed a
divergence of growth characteristics. The no-treatment group of tumors
was significantly larger than the E2-treated
tumors at week 11 of the experiment (week 6 of treatment; Fig. 1B)
.
The observation that E2 caused tumor regression
rather than tumor growth in the MCF-7TAM tumor raised the question that
the animals rather than the tumor had altered over the past 10 years
(5)
. To exclude this possibility, we used a
bitransplantation technique we used previously to demonstrate the
target site specificity of TAM in breast and endometrial tumors
(19)
. Two groups of 10 mice were bitransplanted with
MCF-7TAM and MCF-7TAM2 (a newly TAM-stimulated MCF-7 tumor) and treated
with either E2 (1-cm capsule; premenopausal
levels) or TAM (1.5 mg/day). Both MCF-7TAM and MCF-7TAM2 tumors grew in
response to TAM, but only MCF-7TAM2 grew in response to
E2 (Fig. 2)
. Thus,
early TAM-stimulated tumors can use either E2 or
TAM to grow, but long-term TAM-stimulated tumors can only use TAM.
However, do MCF-7TAME tumors that regrow during
E2 treatment respond to TAM treatment?
|
. The TAM
doses were based on studies published previously (6
, 13)
.
Tumor growth was observed in the E2-treated
group, but both doses of TAM (0.5 and 1.5 mg/day) blunted
E2-stimulated growth. The higher dose of TAM was
more effective in blunting growth. In the second experiment, the mice
were divided into the same four groups as above, but an
E2 (0.3 cm; premenopausal levels) capsule was
used (Fig. 3B)
. Our goal was to establish that a lower dose
of E2 could be blocked more effectively by TAM.
Tumor growth in the E2 group was similar to that
seen with the E2 (1-cm) capsule group, and tumor
size reached a mean tumor size of 1.3 cm2 at 9
weeks. Similar growth rates as the first experiment were seen in the
E2 plus TAM 0.5 mg/day and
E2 plus TAM 1.5 mg/day groups, and once again the
higher dose of TAM (1.5 mg/day) was more effective in suppressing
E2-stimulated growth. It appears that the
MCF-7TAME tumors have evolved from exclusive TAM dependence to
E2 responsiveness with TAM now acting as an
antiestrogen again.
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. TAM-treated MT2 tumors
were retransplanted into new athymic mice and once again treated with
TAM, E2, or vehicle for 11 weeks (Fig. 4B)
. Both E2 and TAM stimulated
growth; however, there was a difference in mean tumor size at 11 weeks
between the TAM- and E2-treated groups (1.02
versus 0.58 cm2, respectively;
P = 0.08). However, this did not reach statistical
significance. In the third experiment, TAM-treated tumors were
retransplanted into new athymic mice and treated with the same doses of
TAM and E2 for 10 weeks (Fig. 4C)
.
Tumor growth was observed in the TAM-treated group, and at 10 weeks the
mean tumor size was 0.35 cm2, whereas no tumor
growth was observed in the E2-treated group, even
at 10 weeks (0.08 cm2; P =
0.0005). The difference between these two groups was statistically
significant. It was clear that E2 had gradually
lost its ability to stimulate tumor growth, although TAM still
maintained its stimulatory effect. By the end of the third experiment,
E2 suppressed tumor growth, a phenomenon observed
previously only in the MCF-7TAM tumors.
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40
ng/ml to maintain tumor growth (12)
. MT2 tumors were
implanted into athymic mice and divided into the following groups: TAM
(2-cm capsule); E2 (0.3- and 1-cm capsule; post-
and premenopausal levels, respectively); or an E2 pellet
(pharmacological estrogen), and treated for 11 weeks (Fig. 5)
. We reported previously the
E2 levels produced by these different
E2 regimens: 83, 379, and 1044 pg/ml,
respectively (13)
. As expected, tumors grew with the TAM
capsule, reaching a mean tumor size of 0.6 cm2 at
11 weeks. However, all E2-treated groups
exhibited little or no tumor growth. However, like the MCF-7TAM tumors,
some MT2 tumors regrew in the E2 1-cm capsule
(premenopausal levels) group after 13 weeks of E2
treatment. The fact that only tumors from the E2
1-cm capsule group grew indicated that the phenomenon of selection was
random rather then related to the concentration of
E2.
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. In
the first experiment, athymic mice were implanted with MT2E tumors and
treated with an E2 1-cm capsule (premenopausal
levels), an E2 1-cm capsule plus with TAM 0.5
mg/day, and TAM 0.5 mg/day for 6 weeks (Fig. 6A)
. Tumor growth was observed
in the E2-treated alone group, and TAM 0.5 mg/day
blocked E2-stimulated growth at 6 weeks, although
this effect did not reach statistical significance (0.7
versus 0.45 cm2; P =
0.11). TAM alone stimulated some tumor growth (0.2
cm2) at 6 weeks, demonstrating that TAM is a weak
agonist in this system. To evaluate the effect of a lower dose of
E2, athymic mice were implanted with MT2E tumors
and divided into the same treatment groups as the previous experiment,
but a 0.3-cm E2 capsule (postmenopausal levels)
was used (Fig. 6B)
. Tumor growth was observed in the
E2-treated group, and TAM 0.5 mg/day
significantly suppressed this E2-stimulated tumor
growth but more effectively than seen with the E2
1-cm capsule (0.19 versus 0.4 cm2,
respectively; P = 0.002). TAM blocks the stimulatory
effect of E2; however, higher doses of
E2 can reverse the antiestrogenic effect of TAM.
The MT2 tumors had evolved from pure TAM dependence to
E2 responsiveness, as the MCF-7TAME tumors did.
However, the MT2 tumors provided an opportunity to observe clonogenic
changes in response to E2.
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), demonstrating that the
MT2 tumors had retained their mutated ER during clonal regrowth. On the
other hand, tumor samples from MCF-7TAM tumors in the
E2 and TAM groups produced bands that comigrated
exactly with those produced by amplification of the wild-type ER cDNA
(HEGO). We conclude that the MT2 tumors retained their ER mutation,
despite a phenotypic change in their responsiveness to TAM.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Most laboratory research has focused on the mechanisms of
estrogen-stimulated breast tumor growth, and surprisingly, there is
little information about the mechanism of estrogen-induced tumoricidal
actions. One exception is the T61 breast tumor model established by
Brunner et al. (26, 27, 28, 29)
. Unlike the MCF-7 tumor
cell line, which was derived from a pleural effusion (30)
,
the T61 tumor was derived from a primary breast cancer. T61 tumor
growth in athymic mice is ovarian independent, and both TAM and
E2 inhibit its growth (29)
. In these
studies, tumor inhibition is dose dependent and varies with the
specific doses of estrogen ranging from pharmacological to
physiological (29)
. In our study, only physiological doses
were needed to induce tumor regression or prevent tumor growth. We
suggest that the repeated transplantation of our tumors in TAM-treated
animals has resulted in the selection of an MCF-7 tumor that is now
supersensitive to the cytotoxic effects of estrogen. It is, however,
interesting to note that whatever the mechanisms, our MCF-7TAM tumors
regress after 2 weeks of E2 treatment, a time
course noted by Brunner et al. (26)
with the
T61 tumors. However, MCF-7TAM and MT2 tumors progress through a cycle
of hormonal sensitivity, and the studies reported here have not been
done previously with the T61 tumor. In addition, there was no evidence
that TAM could stimulate the growth of the T61 tumors.
It is important to point out that the mutant ER found in the MT2 tumor
is retained in the E2-selected tumor subline MT2E
(Fig. 7)
. Mutated ERs have been associated with increased estrogenicity
of TAM (9
, 10)
. The MT2 tumors retain the Asp351Tyr
mutation, despite their phenotypic change from TAM-stimulated growth
(MT2) to E2-stimulated growth and TAM-inhibited
growth (MT2E). We must, therefore, conclude that other cellular factors
are essential for the development of the MT2 TAM-stimulated phenotype.
The fact that wild-type ER predominates in the MCF-7TAM-stimulated
tumor suggests that a mutant receptor is only one of the many potential
supporting mechanisms for drug resistance to TAM.
An examination of the interaction of TAM and E2
illustrates an important point about the therapeutic effectiveness of
TAM as a competitive inhibitor of E2 action. We
have reported the competition between E2 and TAM
in vivo previously (12)
, and it is important
clinically when considering TAM therapy in premenopausal women
(17
, 31)
. High doses of E2 can
potentially render the antitumor activity of TAM less effective. In the
experiments evaluating TAM action in the second generation of MCF-7TAME
tumors, higher doses of TAM (1.5 versus 0.5 mg/day) were
more effective in suppressing E2-stimulated
growth (Fig. 4, A and B)
. In the experiments
evaluating TAM action in MT2E tumors (Fig. 6, A and B)
, in which the TAM dose was held constant but the
E2 dose changed, a 1-cm E2
capsule (premenopausal levels) was more effective in reversing the
antitumor effect of TAM than a 0.3-cm E2 capsule
(postmenopausal levels). This is powerful evidence that the
effectiveness of the antiestrogenic effect of TAM is dependent on the
relative concentration of E2 and TAM. A 1-cm
E2 capsule produces E2
levels (379 pg/ml) equivalent to that of a premenopausal woman
(150–350 pg/ml; Ref. 17
), whereas a 0.3-cm
E2 capsule produces levels (83.8 pg/ml)
equivalent to that of a postmenopausal woman (13)
. Perhaps
TAM would be more effective in a premenopausal woman if estrogen levels
were lowered. Some evidence to support this position has been obtained
recently by comparing the action of TAM with TAM plus a luteinizing
hormone-releasing hormone agonist to produce a medical oophorectomy.
The theoretically combined therapy is superior (32)
, and a
preliminary clinical report supports this view (33)
.
We believe it is appropriate to advance a cyclic model of hormone
dependency in breast cancer that is based on our experiences with
transplantable MCF-7 breast tumors over the past decade (Fig. 8)
. The
transition from estrogen- to TAM-stimulated tumor growth occurs in some
tumors within a year of TAM treatment, but the important observation we
now report is the reproducible change from TAM-stimulated growth to
E2-inhibited growth. Some breast cancer cells
then revert back to estrogen-stimulated growth, and TAM, once again,
blocks estrogen-stimulated tumor growth.
Stoll (34)
has described previously the regression of
tumors during high-dose estrogen therapy, but the tumor eventually
regrows, only to regress again when estrogen is removed. Patients can
be palliated by intermittent estrogen and withdrawal over many years.
Our laboratory results are a variation of this clinical observation,
because the physiological estrogen is key to tumor regression after TAM
failure. Estrogen treatment is superior to simply withdrawing TAM
treatment (Figs. 1B
and 5)
. Another potentially important
point is the return of the resistant tumor to TAM sensitivity. It is
possible that patients could be maintained on TAM, with episodic
periods of estrogen treatment. However, this hypothesis can only be
validated through the clinical trials process.
The question of a mechanism to explain the actions of E2 and TAM as antitumor agents is not a simple issue to answer. The mechanism of TAM-stimulated tumor growth must involve two components: a selection of cells that grow in response to the partial agonist actions of TAM; and a second requirement for estrogen-like angiogenesis to support tumor growth. TAM-stimulated tumors have an increased activation of the VEGF gene (35) , which is an important component for angiogenesis. The mechanism of E2-induced tumor cell death is also unclear. Indeed, a mechanism for the antitumor action of pharmacological doses of estrogen has never been solved.
The recent discovery of a second ER referred to as ER ß
(36)
introduces a new dimension for the understanding of
estrogen action. ER ß has a structural organization similar to ER
, the classical ER (36)
, but there are important
differences in the activating functions (37
, 38)
and the
ligand-binding domains (39, 40, 41, 42)
. Most importantly, ER ß
and ER are able to activate an AP-1 signal transduction pathway
with TAM (43, 44, 45)
, which might be able to amplify the
agonist actions of TAM to induce TAM-stimulated growth. However,
E2 inhibits ER ß AP-1 pathways (44
, 45)
; therefore, it is plausible that this could be a mechanism
for the tumoricidal actions of E2. Long-term
TAM-stimulated tumors, such as MCF-7TAM and MT2, could contain cells
selected for the ER ß AP-1 pathways. It is difficult to test this
hypothesis directly without reliable monoclonal antibodies to
quantitate ER ß, but it is possible to test the hypothesis
experimentally. The pure antiestrogen ICI 182,780 stimulates the ER ß
AP-1 pathway (43, 44, 45)
; therefore, if the pathway is
critical for TAM-stimulated tumors after 5 years of treatment, then ICI
182,780 should stimulate and not block tumor growth. Only about half of
the ER -positive tumors that fail TAM respond to ICI 182,780 with
tumor regression (46
, 47)
. Perhaps, tumor growth is
supported by an activated AP-1 pathway in the tumors that progress. We
are currently testing our hypothesis.
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FOOTNOTES |
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1 Supported by the Lynn Sage Foundation of
Northwestern Memorial Hospital and the Avon Breast Cancer Fund. 
2 Present address: Department of General Surgery,
Korea University Ansan Hospital, 516 Kojan-Dong Ansan city Kyunggi-Do,
425-020, South Korea.
3 To whom requests for reprints should be
addressed, at the R. H. Lurie Comprehensive Cancer Center,
Northwestern University Medical School, 710 North Fairbanks, Olson
8258, Chicago, IL 60610. Phone: 312-908-4148; Fax: 312-908-1372.
4 The abbreviations used are: TAM, tamoxifen;
NSABP, National Surgical Breast and Bowel Project; E2,
estradiol; ER, estrogen receptor; PEG, polyethylene glycol; SSCP,
single-stranded conformational polymorphism; DES, diethylstilbestrol.
Received 8/31/99; revised 1/31/00; accepted 2/16/00.
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REFERENCES |
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|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
mRNA in MDA-MB-231 breast cancer cells stably expressing the oestrogen receptor. Br. J. Cancer, 77: 1812-1819, 1998.[Medline]
receptor chimeras. Endocrinology, 139: 4513-4522, 1998. transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens. Endocrinology, 140: 5566-5578, 1999. and ß. Endocrinology, 138: 863-870, 1997. and estrogen receptor ß to partial estrogen agonists/antagonists. Mol. Pharmacol., 54: 105-112, 1998. and ERß at AP-1 sites. Science (Washington DC), 277: 1508-1510, 1997.This article has been cited by other articles:
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|
|
|
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|
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|
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|
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|
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|
|
|
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|
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|
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|
|
|
|
 |
|
 N. C. Peterson, M. D. Servinsky, A. Christian, Z. Peng, W. Qiu, J. Mann, J. Dicello, and D. L. Huso Tamoxifen resistance and Her2/neu expression in an aged, irradiated rat breast carcinoma model Carcinogenesis, September 1, 2005; 26(9): 1542 - 1552. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
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|
V. C. Jordan, C. Osipo, D. Cheng, and J. S. Lewis RESPONSE: Re: Playing the Old Piano: Another Tune for Endocrine Therapy J Natl Cancer Inst, April 7, 2004; 96(7): 556 - 557. [Full Text] [PDF]
|
|
|
|
|
|
L. M. Berstein, J.-P. Wang, H. Zheng, W. Yue, M. Conaway, and R. J. Santen Long-Term Exposure to Tamoxifen Induces Hypersensitivity to Estradiol Clin. Cancer Res., February 15, 2004; 10(4): 1530 - 1534. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Liu, E.-S. Lee, C. Gajdos, S. T. Pearce, B. Chen, C. Osipo, J. Loweth, K. McKian, A. De Los Reyes, L. Wing, et al. Apoptotic Action of 17{beta}-Estradiol in Raloxifene-Resistant MCF-7 Cells In Vitro and In Vivo J Natl Cancer Inst, November 5, 2003; 95(21): 1586 - 1597. [Abstract] [Full Text] [PDF]
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C. Osipo, C. Gajdos, H. Liu, B. Chen, and V. C. Jordan Paradoxical Action of Fulvestrant in Estradiol-Induced Regression of Tamoxifen-Stimulated Breast Cancer J Natl Cancer Inst, November 5, 2003; 95(21): 1597 - 1608. [Abstract] [Full Text] [PDF]
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|
|
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|
J. Faridi, L. Wang, G. Endemann, and R. A. Roth Expression of Constitutively Active Akt-3 in MCF-7 Breast Cancer Cells Reverses the Estrogen and Tamoxifen Responsivity of these Cells in Vivo Clin. Cancer Res., August 1, 2003; 9(8): 2933 - 2939. [Abstract] [Full Text] [PDF]
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V. C. Jordan Is Tamoxifen the Rosetta Stone for Breast Cancer? J Natl Cancer Inst, March 5, 2003; 95(5): 338 - 340. [Full Text] [PDF]
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T. Bachleitner-Hofmann, B. Pichler-Gebhard, M. Rudas, M. Gnant, S. Taucher, D. Kandioler, E. Janschek, P. Dubsky, S. Roka, E. Sporn, et al. Pattern of Hormone Receptor Status of Secondary Contralateral Breast Cancers in Patients Receiving Adjuvant Tamoxifen Clin. Cancer Res., November 1, 2002; 8(11): 3427 - 3432. [Abstract] [Full Text] [PDF]
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 T. D. Shanafelt, D. L. Barton, A. A. Adjei, and C. L. Loprinzi Pathophysiology and Treatment of Hot Flashes Mayo Clin. Proc., November 1, 2002; 77(11): 1207 - 1218. [Abstract] [PDF]
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V. C. Jordan, H. Liu, and R. Dardes Re: Effect of Long-Term Estrogen Deprivation on Apoptotic Responses of Breast Cancer Cells to 17{beta}-Estradiol and The Two Faces of Janus: Sex Steroids as Mediators of Both Cell Proliferation and Cell Death J Natl Cancer Inst, August 7, 2002; 94(15): 1173 - 1173. [Full Text] [PDF]
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A. M. Soto and C. Sonnenschein RESPONSE: Re: Effect of Long-Term Estrogen Deprivation on Apoptotic Responses of Breast Cancer Cells to 17{beta}-Estradiol and The Two Faces of Janus: Sex Steroids as Mediators of Both Cell Proliferation and Cell Death J Natl Cancer Inst, August 7, 2002; 94(15): 1174 - 1175. [Full Text] [PDF]
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R. C. Dardes, R. M. O'Regan, C. Gajdos, S. P. Robinson, D. Bentrem, A. De Los Reyes, and V. C. Jordan Effects of a New Clinically Relevant Antiestrogen (GW5638) Related to Tamoxifen on Breast and Endometrial Cancer Growth in Vivo Clin. Cancer Res., June 1, 2002; 8(6): 1995 - 2001. [Abstract] [Full Text] [PDF]
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R. M. O'Regan, C. Gajdos, R. C. Dardes, A. De Los Reyes, W. Park, A. W. Rademaker, and V. C. Jordan Effects of Raloxifene After Tamoxifen on Breast and Endometrial Tumor Growth in Athymic Mice J Natl Cancer Inst, February 20, 2002; 94(4): 274 - 283. [Abstract] [Full Text] [PDF]
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R. X.-D. Song, G. Mor, F. Naftolin, R. A. McPherson, J. Song, Z. Zhang, W. Yue, J. Wang, and R. J. Santen Effect of Long-Term Estrogen Deprivation on Apoptotic Responses of Breast Cancer Cells to 17{beta}-Estradiol J Natl Cancer Inst, November 21, 2001; 93(22): 1714 - 1723. [Abstract] [Full Text] [PDF]
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M. J. Chisamore, Y. Ahmed, D. J. Bentrem, V. C. Jordan, and D. A. Tonetti Novel Antitumor Effect of Estradiol in Athymic Mice Injected with a T47D Breast Cancer Cell Line Overexpressing Protein Kinase C{alpha} Clin. Cancer Res., October 1, 2001; 7(10): 3156 - 3165. [Abstract] [Full Text] [PDF]
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D. J. Bentrem, R. C. Dardes, H. Liu, J. MacGregor-Schafer, J. W. Zapf, and V. C. Jordan Molecular Mechanism of Action at Estrogen Receptor {{alpha}} of a New Clinically Relevant Antiestrogen (GW7604) Related to Tamoxifen Endocrinology, February 1, 2001; 142(2): 838 - 846. [Abstract] [Full Text] [PDF]
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E. S. Lee, J. M. Schafer, K. Yao, G. England, R. M. O’Regan, A. D. L. Reyes, and V. C. Jordan Cross-Resistance of Triphenylethylene-type Antiestrogens but not ICI 182,780 in Tamoxifen-stimulated Breast Tumors Grown in Athymic Mice Clin. Cancer Res., December 1, 2000; 6(12): 4893 - 4899. [Abstract] [Full Text]
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