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Endocrinology |
Ligands Inhibit Estrogen Biosynthesis in Human Breast Adipose Tissue: Possible Implications for Breast Cancer Therapy1
Victorian Breast Cancer Research Consortium, Inc., Prince Henry’s Institute of Medical Research, Clayton, Victoria 3168, Australia [G. L. R., E. R. S.]; Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9051 [Y. Z.]; and The Plastic & Aesthetic Surgery Centre, Windsor, Victoria 3181, Australia [A. M. K.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. These cytokines, which are expressed
in adipose, also inhibit adipocyte differentiation. Therefore, we
hypothesized that factors which stimulate adipocyte differentiation
should inhibit aromatase expression. These factors include synthetic
peroxisome proliferator-activated receptor 
(PPAR) ligands such
as thiazolidinediones, e.g., troglitazone and
rosiglitazone (BRL49653) and the endogenous PPAR ligand
15-deoxy-
12,14-prostaglandin J2. We have
demonstrated by measurement of aromatase activity and by reverse
transcription-PCR/Southern blotting that these PPAR ligands inhibit
aromatase expression in cultured breast adipose stromal cells
stimulated with oncostatin M or tumor necrosis factor plus
dexamethasone in a concentration-dependent manner, whereas a metabolite
of troglitazone that does not activate PPAR has no effect. We have
also shown that troglitazone inhibits luciferase activity of reporter
constructs containing various lengths of the upstream region of
promoter I.4 transfected into mouse 3T3-L1 preadipocyte mesenchymal
cells, whereas the troglitazone metabolite does not. Because local
estrogen production in breast fat is implicated in breast cancer
development in postmenopausal women, the actions of PPAR ligands
suggest that they may have potential therapeutic benefit in the
treatment and management of breast cancer. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Estrogen biosynthesis is catalyzed by the enzyme aromatase
(Refs. 1, 2, 3, 4
; aromatase cytochrome P-450; the product of
the CYP19 gene; Ref. 5
). CYP19 is a
member of the P-450 superfamily of genes, which currently contains over
600 members in some 40 gene families (6)
. Aromatase is
responsible for catalyzing the aromatization of the A ring of
C19 androgens to the phenolic A ring of
C18 estrogens, resulting in loss of the
C19 angular methyl group as formic acid
(7)
. In humans, aromatase is expressed in a variety of
tissues including: the granulosa cells and corpus luteum of the ovary
(8
, 9)
; the Leydig cells and germ cells of the testis
(10
, 11)
; the syncytiotrophoblast of the placenta
(8)
; various sites in the brain including the hypothalamus
and hippocampus (12
, 13)
; adipose tissue of the breast,
abdomen, thighs, and buttocks (14
, 15)
; and osteoblasts of
bone (16
, 17)
. The human CYP19 gene spans at
least 75 kb, with a coding region of 
35 kb containing nine
translated exons (II-X; Refs. 18, 19, 20
; Fig. 1
). Aromatase transcripts in the various tissue sites of expression
contain different 5'-untranslated first exons because of the use of a
number of alternative promoters that regulate aromatase expression in
the ovary (promoter II; Ref. 9
), placenta (promoter I.1;
Refs. 8
, 21,
and 22
), and adipose tissue
(promoters I.4 and II; Ref. 23
) via alternative splicing
mechanisms. Each promoter is differentially regulated with promoter II
under the control of follicle-stimulating hormone, the actions of which
are mediated by cyclic AMP (24
, 25)
, whereas promoter I.1
is regulated by retinoids (26)
. Expression via promoter
I.4 in adipose tissue requires the synergistic actions of
glucocorticoids and class I cytokines or
TNF3- (27, 28, 29)
. The former uses a Janus-activated kinase
1/STAT3 signaling pathway in which the activated STAT3 binds to a GAS
element located upstream of promoter I.4 (28)
, whereas the
latter uses a mitogen-activated protein kinase/AP-1 pathway, resulting
in binding of c-fos/c-jun to an AP-1 site upstream of the GAS element
(Ref. 29
; Fig. 1
).
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Adipose tissue is the main site of estrogen biosynthesis in
postmenopausal women, and aromatase expression in adipose increases
with age and body weight (14
, 15)
. Local production of
estrogen in breast adipose tissue is implicated in the development of
breast cancer in postmenopausal women (15
, 30)
. Estrogen
levels in breast tumors are as much as 10 times greater than in the
circulation of postmenopausal women (31)
. This appears to
be because aromatase expression within a tumor and the surrounding
breast tissue is elevated as a result of the production of factors by
the tumor which stimulate aromatase expression (32)
.
Aromatase expression in adipose tissue is primarily located in the
mesenchymal stromal cells and appears to be a marker of the
undifferentiated preadipocyte phenotype (33, 34, 35)
.
Consistent with this, factors known to stimulate aromatase expression
in adipose tissue, such as the class I cytokines interleukin 6,
interleukin 11, OSM, as well as TNF-, also inhibit adipocyte
differentiation (36
, 37)
. Conversely, factors that
stimulate adipocyte differentiation would be anticipated to inhibit
aromatase expression. Such factors include ligands of PPAR, such as
the TZDs troglitazone and rosiglitazone, as well as natural
ligands such as 15d-PGJ2 (38
, 39)
.
PPAR is a member of the superfamily of ligand-activated
transcription factors, which includes receptors for steroid, retinoid,
and thyroid hormones, and exists in three different isoforms, 1,
2, and 3. It is abundantly expressed in adipose tissue and plays
a key role in adipocyte differentiation (38, 39, 40)
.
In the present report, we show that TZDs and
15d-PGJ2 do indeed inhibit aromatase expression
in human adipose stromal cells of breast origin, whereas a metabolite
of troglitazone that does not activate PPAR has no action on
aromatase expression. These findings suggest that troglitazone and
other TZDs might have therapeutic utility in the management of breast
cancer in postmenopausal women.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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ligands troglitazone (Parke-Davis, Ann Arbor, MI), rosiglitazone
(BRL49653), or 15d-PGJ2 (Cayman Chemical Co., Ann
Arbor, MI) at varying concentrations. Cells were either assayed for
aromatase activity or harvested for total RNA.
Aromatase Assay.
Aromatase activity was determined after incubation of cells
with [1ß-3H]androstenedione (NEN Life Science
Products, Inc., Boston, MA) for 2 h and measured by the
incorporation of tritium into [3H]water (NEN),
as described previously (33)
.
RT-PCR and Southern Blot Analysis.
After treatment, total RNA was extracted from human breast
adipose stromal cells using the RNeasy Mini kit (Qiagen, Melbourne,
Victoria, Australia), according to the manufacturer’s instructions.
Total RNA (0.25 µg) was reverse transcribed using the Superscript
One-Step RT-PCR system (Life Technologies, Inc., Melbourne, Victoria,
Australia) as described by the manufacturer, using the
aromatase-specific primers (Pacific Oligos, Sydney, New South Wales,
QLD, Australia): 5'-sense from exon I.4 (5'-GTG ACC AAC TGG AGC
CTG-3'); 5'-sense from exon II (5'-TTG GAA ATG CTG AAC CCG-3'); and
3'-antisense from exon III (5'-CAG GAA TCT GCC GTG GGA GA-3'). Product
amplification was determined as a function of the number of cycles to
derive the linear range. On the basis of this information,
amplification was routinely continued for 30 cycles. Integrity of cDNA
was checked by amplification of the GAPDH gene using
the GAPDH-specific primers (Pacific Oligos, Sydney, New South Wales):
5'-sense (5'-CGG AGT CAA CGG ATT TGG TCG TAT-3') and 3'-antisense
(5'-AGC CTT CTC CAT GGT GGT GAA GAC-3'). The PCR products were
subjected to electrophoresis and blotted onto Hybond-N+ (Amersham
Pharmacia Biotech, Sydney, New South Wales, Australia; Ref.
41
). For quantitation, membranes were hybridized with
specific 32P-labeled oligoprobes to aromatase
exon II (5'-CAT CAC CAG CAT CGT GCC TG-3') and GAPDH (5'-AAG ATG GTG
ATG GGA TTT CC-3') labeled by T4 polynucleotide kinase (Life
Technologies) and [-32P]ATP (NEN). Aromatase
expression was quantitated (arbitrary units) by phosphorimaging
(Bio-imaging analyzer MacBAS v2.4; Fujifilm) and normalized against
GAPDH.
Transient Transfection and Reporter Gene Assays.
3T3-L1 cells, a mouse preadipocyte fibroblast cell line
(ATCC CL-173) were cultured in DMEM supplemented with 10% FBS
at a density of 40,000 cells/ml. 3T3-L1 cells were transfected for
22 h with 1.5 µg of a chimeric DNA reporter gene construct
containing 774 bp of the 5'-regulatory region upstream of promoter I.4
of the human CYP19 gene fused to a Luc reporter gene in the
pGL3 vector (a generous gift from Dr. Makio Shozu, Kanazawa University,
Kanazawa, Japan) and 0.5 µg of pSV-ß-galactosidase control vector
(Promega, Sydney, New South Wales, Australia) using FuGENE 6
Transfection Reagent (Roche Diagnostics Australia Pty. Ltd., Victoria,
Melbourne, Australia) according to manufacturer’s instructions. After
serum starvation, cells were stimulated with Dex and OSM for 8 h
and treated in the presence or absence of troglitazone or troglitazone
metabolite. Cells were then lysed, and relative Luc activity was
measured and normalized to ß-galactosidase activity (Promega).
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Ligands Inhibit Aromatase Activity in Human Breast Adipose
Stromal Cells. ligands on aromatase activity in human
breast adipose stromal cells was determined. Basal levels of aromatase
activity in these cells are low but can be markedly up-regulated in the
presence of both glucocorticoids and class I cytokines or TNF-
(28
, 29) . The PPAR ligands troglitazone, rosiglitazone
(BRL49653), and 15d-PGJ2 inhibited Dex- and
OSM-stimulated aromatase activity in human breast adipose stromal cells
in a concentration-dependent manner, whereas a troglitazone metabolite
that was not a PPAR ligand had no effect (Fig. 2A)
. Similar results were obtained when TNF- was
substituted for OSM (Fig. 2B)
. The endogenous PPAR ligand
15d-PGJ2 was the most potent inhibitor of
aromatase activity, with an IC50 of <1
µM. Concentrations of
15d-PGJ2 >2 µM
completely abolished aromatase activity, whereas concentrations <100
nM had little effect. The synthetic PPAR
ligand troglitazone inhibited aromatase activity with an
IC50 of <10 µM.
Concentrations of troglitazone >10 µM
completely abolished aromatase activity. To demonstrate that this was
not an action of troglitazone to inhibit the catalytic activity of the
aromatase enzyme directly, a time course of the inhibitory action of
troglitazone was determined (data not shown). Troglitazone only blocked
the induction of aromatase activity by Dex and OSM after an incubation
of 24 h or greater. Troglitazone had no effect on aromatase
activity when it was added simultaneously with the aromatase substrate
[1ß-3H]androstenedione.
|
Ligands Inhibit Aromatase Expression in Human Breast
Adipose Stromal Cells.
. Aromatase expression in breast adipose
stromal cells is very low but is markedly stimulated by both Dex and
OSM. Treatment of Dex/OSM-stimulated adipose stromal cells with
troglitazone indicated that aromatase expression via promoter I.4 is
inhibited in a concentration-dependent manner and is almost completely
abolished at concentrations >10 µM (Fig. 3A)
. 15d-PGJ2 also inhibited
Dex/OSM-stimulated aromatase expression in a concentration-dependent
manner and dramatically reduced aromatase expression at >2
µM (Fig. 3B)
. No effect on the
expression level of the housekeeping gene GAPDH was observed
with either ligand. Both PPAR ligands inhibited aromatase expression
in a similar concentration range to that observed for inhibition of
aromatase activity. Similar results were obtained when the coding
region of aromatase was amplified using the 5'-primer to exon II (Fig. 3, C and D)
.
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ligands interfere
with the transcription of the aromatase gene via
promoter I.4, 3T3-L1 cells were transfected with either a
Luc reporter gene fused to -774 bp of the 5'-regulatory
region of promoter I.4 of the CYP19 gene in the pGL3 vector
or else the pGL3-basic vector. Fig. 4
demonstrates that in the absence of treatment, basal levels of
Luc gene expression were observed in cells transfected
with both pGL3-basic vector and -774/+14 P450-I.4/Luc. Treatment with
Dex and OSM (which up-regulate aromatase expression through promoter
I.4) caused a 5-fold induction in Luc gene expression.
Troglitazone caused a concentration-dependent inhibition of
Luc gene expression with concentrations >10
µM, reducing expression to basal levels. This
result was consistent with the effect of troglitazone on aromatase
activity (Fig. 2)
and expression (Fig. 3)
. Treatment with troglitazone
had no effect on basal Luc or ß-galactosidase expression, and
treatment with a 0.1% DMSO vehicle did not affect Luc activity.
|
., 3T3-L1 cells were transfected with the
same Luc reporter gene constructs, -774/+14 P450-I.4/Luc or
pGL3-basic vector, and treated with troglitazone and a troglitazone
metabolite that is unable to bind to the receptor. Troglitazone
inhibited transcription via promoter I.4 in a concentration-dependent
manner as before, whereas the troglitazone metabolite had no
effect on gene expression at any concentration (Fig. 5)
, similar to the results obtained in terms of aromatase activity (Fig. 2)
.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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is a key transcription factor involved in adipocyte
differentiation (38
, 39)
. Because of their ability to
increase the responsiveness of insulin-sensitive cells to insulin,
ligands for PPAR have been actively studied for their therapeutic
utility in the treatment of insulin-resistant diabetes, and currently
one of these, namely troglitazone, is in clinical use in the United
States for this purpose. More recently it has been found that PPAR
ligands can stimulate differentiation of a number of cell types and not
only those of mesenchymal origin, e.g., colon cancer cells
(42)
as well as breast cancer cell lines
(43)
, suggesting that PPAR ligands could have
therapeutic utility in the treatment of certain forms of cancer.
Indeed, in a recent clinical trial of patients with advanced
liposarcoma, it was found that troglitazone can stimulate the
differentiation of such tumors in vivo (44)
.
The observation that PPAR ligands can stimulate the differentiation
of breast cancer cell lines (43)
suggests that these
compounds might have utility in breast cancer therapy.
The results presented here provide independent data in support
of this contention, i.e., that PPAR ligands inhibit the
expression of aromatase and hence estrogen biosynthesis in adipose
tissue, and in particular adipose tissue of the human breast. Aromatase
expression is a marker of the undifferentiated preadipocyte mesenchymal
phenotype (33, 34, 35)
and as such is stimulated by factors
that inhibit adipocyte differentiation, such as class I cytokines and
TNF-, a number of which are synthesized in adipose tissue itself
(36
, 37) . Consequently, it was anticipated that factors
that stimulate adipocyte differentiation and increase the expression of
differentiation markers, such as lipoprotein lipase and the insulin
receptor, would also inhibit aromatase expression in adipose
mesenchymal cells. The results presented here show that this is indeed
the case; aromatase expression stimulated by class I cytokines or
TNF- is inhibited by several PPAR ligands in a
concentration-dependent fashion, whereas a troglitazone metabolite,
which is not a PPAR ligand, had no effect on aromatase expression.
The results of transfection experiments using chimeric constructs in
which the Luc reporter gene is regulated by the aromatase
promoter I.4 indicate that this inhibition is a consequence of
interaction with the cell signaling pathways involving Janus-activated
kinase 1 and STAT3 in the case of the class I cytokines, and AP-1 in
the case of TNF. Interactions of PPAR with these signaling
pathways have previously been described in other systems, for example
in a monocyte cell lineage, PPAR interferes with IFN- action via
a STAT1- and AP-1-mediated pathway (45)
. The mechanism
whereby PPAR inhibits cytokine-stimulated aromatase expression via
promoter I.4 in adipose stromal cells remains to be elucidated. One
possibility is that it competes with the STAT3 and AP-1 pathways for
CREB-binding protein, which appears to play a universal role in
mediating the transcriptional responses of genes to multiple signaling
pathways. This possibility is currently under investigation.
The results presented here suggest that PPAR ligands could
find utility in breast cancer therapy. Presently, most breast cancer
hormonal therapies are directed to inhibition of estrogen action or
inhibition of aromatase activity. Estrogen receptor antagonists such as
tamoxifen display selectivity in the tissue site of action, but
generally after several years of treatment, breakthrough occurs with
clonal tumor lines developing that are unresponsive to tamoxifen.
Aromatase inhibitors are used as second-line therapy and also have
potential as first-line adjuvant therapy but have the disadvantage that
they inhibit aromatase indiscriminately in all tissue sites including
bone and brain, where they may have adverse effects in terms of bone
mineralization on the one hand and possibly cognitive function on the
other. Because aromatase expression is regulated differently in
different tissue sites through the use of different tissue-specific
promoters (35)
, the possibility is presented that
tissue-selective inhibitors of aromatase expression could be developed.
Whether PPAR ligands will demonstrate sufficient tissue selectivity
to warrant their development as breast cancer therapeutic agents
remains to be determined, but results presented here are
sufficiently encouraging to warrant further investigation.
|
ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by a grant from The Victorian Breast
Cancer Research Consortium, Inc. (Anti-Cancer Council of Victoria,
Australia) and by USPHS Grant R37-AG08174. 
2 To whom requests for reprints should be
addressed, at Prince Henry’s Institute of Medical Research, P. O. Box
5152, Clayton, Victoria 3168, Australia. Phone: 61-3-9594-3570; Fax:
61-3-9594-6125; E-mail: Gary.Rubin{at}med.monash.edu.au
3 The abbreviations used are: TNF, tumor necrosis
factor; STAT, signal transducers and activators of transcription; GAS,
IFN- activating sequence; OSM, oncostatin M; PPAR, peroxisome
proliferator-activated receptor ; TZD, thiazolidinedione;
15d-PGJ2, 15-deoxy-12,14-prostaglandin
J2; RT-PCR, reverse transcription-PCR; GAPDH,
glyceraldehyde-3-phosphate dehydrogenase; Dex, dexamethasone; Luc,
luciferase; AP-1, activating protein-1.
Received 8/30/99. Accepted 1/18/00.
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