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Original Studies |
Departments of Physiology and Cell Biology (J.-Y.C., R.K., E.L.M., S.M.J.), Surgery (W.E.B.), College of Medicine, and Veterinary Clinical Sciences (R.L.), Ohio State University, Columbus, Ohio 43210; INSERM, Faculté de Médecine Lyon-RTH Laennec (B.R.), 69372 Lyon, France; and National Hormone and Pituitary Program, Harbor-University of California Medical Center Research and Education Institute (A.F.P.), Torrance, California 90502
Address all correspondence and requests for reprints to: Sissy M. Jhiang, Ph.D., Department of Physiology and Cell Biology, Ohio State University, 302 Hamilton Hall, 1645 Neil Avenue, Columbus, Ohio 43210-1218. E-mail: jhiang.1{at}osu.edu
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Introduction |
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The thyroid is not the only tissue that shows radioiodide uptake (RAIU) activity. RAIU has been demonstrated in various extrathyroidal tissues, such as lactating mammary gland. It has been shown that breast atypia and malignancy have increased RAIU (2), and that breast cancers can be detected by radioiodide/99mTc scintigraphy (3, 4). Furthermore, one study indicates that high RAIU may prove to be the most specific biochemical characteristic of hormone-dependent breast tumors compared to hormone-independent tumors (5). The fact that RAIU is significantly increased in lactating breast tissues (6) suggests that RAIU is also subject to hormonal control in breast tissues, and that RAIU activity and Na+/I- symporter (NIS) expression may be stimulated by hormones involved in active lactation.
NIS is the molecule that mediates RAIU in target cells such as thyroid, salivary gland, and breast. Molecular cloning of NIS (7, 8) has made it possible to investigate hormonal control of NIS expression in breast tissues. As RAIU in breast is at its maximum when women are undergoing active lactation, hormones involved in active lactation are the most likely candidates to induce NIS expression in breast. PRL is the most important hormone for lactogenesis, and oxytocin (OT) is the essential hormone to maintain active lactation. An increased expression of PRL receptor (PRLR) has been documented in some human breast tumors and human breast cancer cell lines (9, 10, 11). Although oxytocin receptor (OTR) is expressed in myoepithelial cells in normal breast tissues, it has been reported to be expressed in human breast tumors (12, 13, 14). In this study we investigated both RAIU and NIS expression in rat mammary glands of various stages and the possible effects of PRL and OT on RAIU and NIS expression in breast tissues.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Sprague Dawley rats were purchased from Harlan Sprague Dawley, Inc. (Indianapolis, IN), and housed in the animal vivarium facility at the Ohio State University. All animal studies were approved by the Ohio State University institutional laboratory animal care and use committee. For oxytocin antagonist treatment, lactating rats were injected ip with a selective oxytocin antagonist, des Gly-NH2,d(CH2)5[D-Tyr2,Thr4]OVT (OTA) (15) at a dosage of 3 µg in 300 µL/injection. For bromocriptine (Br-CT) treatment (Sigma, St. Louis, MO), lactating rats were injected ip with Br-CT at a dosage of 0.6 mg in 300 µL/injection. For Br-CT plus OTA treatment, lactating rats were injected ip with 0.6 mg Br-CT and 3 µg OTA in 300 µL/injection. Every rat was injected twice a day for 1 week (lactating days 4.5–11.5). Control animals were injected with the same volume of saline. Each experimental group had three rats.
In vivo 99mTc scintigraphy
Rats were anesthetized with inhalation of isoflurane, and then
1.5 mCi 99mTc-pertechnetate
(99mTcO4-)
in 0.2 mL volume were administered via tail vein injection. Rats were
placed in a prone position on a 
-camera (QRS Systems, Nuclear
Medicine Diagostics Systems Laboratories, Inc., San
Antonio, TX) with a 140-keV high resolution collimator interfaced to a
Macintosh computer-based nuclear medicine imaging system (NucLear MAC
2.9, Scientific Imaging, Littleton, CO). The images were obtained at 20
min postinjection of
99mTcO4-
with a 2-min acquisition time.
Radioiodide uptake assay and radioiodide organification assay
NIS functional activity in mammary gland was assessed by RAIU,
the sum total of iodide influx and efflux in 1 h.
125I- was ip administered
to rats at 0.3 µCi (in 0.2 mL phosphate-buffered saline)/g BW. Rats
were sacrificed 1 h later, and tissues, including axillary and
inguinal mammary glands, were collected to measure radioactivity
using a -counter (Packard Instruments, Downers Grove, IL). The data
were presented as a fold increase in radioactivity, compared to spleen,
by the following formula: (counts/mg for mammary gland)/(counts/mg
for spleen). Radioiodide organification assay was performed as
previously described (16).
RIA for rat serum PRL (rPRL)
After drug treatment, blood was collected from the tail vein before RAIU assay, and sera were stored at -80 C before rPRL RIA. For rPRL RIA, a double antibody method was employed, using highly purified rPRL, AFP4459B, as the iodinated ligand, rabbit anti-rPRL, NIDDK S-9, AFP131581570, as the primary antibody, and rPRL AFP4459B, NIDDK rPRL RP-3 as the cold standard or reference preparation. These RIA immunoreagents are distributed by the NIDDK National Hormone and Pituitary Program, gratis, to researchers on request (consult website http://www.humc.edu/hormones for additional information).
Western blot analysis
Western blot analysis was performed as previously described (17) with some modifications. Briefly, frozen tissues were pounded in a vinyl bag, homogenized, and sonicated (20 s) in a lysis buffer (50 mmol/L Tris (pH 8.0), 150 mmol/L NaCl, 1 mmol/L ethylenediamine tetraacetate, 1% Nonidet P-40, 100 µg/mL phenylmethylsulfonylfluoride, 1 µg/mL aprotinin, and 1 µg/mL leupeptin). The lysates were centrifuged at 12,000 x g for 20 min at 4 C. The supernatants (100 or 200 µg/lane) were solubilized for 30 min at 37 C in the same volume of reducing sample buffer (0.125 mol/L Tris-HCl (pH 6.8), 4% SDS, 10% ß-mercaptoethanol, and 20% glycerol) and subjected to 7.5% SDS-PAGE. Western blot analysis was then performed by incubating the filter with an anti-rNIS peptide polyclonal antibody pAb 716 (1:5000) generated by Dr. Bernard Rousset (18) in Tris-buffered saline with 0.1% Tween-20 containing 5% nonfat dry milk for 1.5 h at room temperature, followed by incubation with horseradish peroxidase-conjugated donkey anti-rabbit IgG (1:4000) for 1 h at room temperature. For deglycosylation of the proteins, 100 or 200 µg proteins were denatured in the denaturing buffer (0.5% SDS and 1% ß-mercaptoethanol) for 30 min at 37 C. Denatured proteins were treated with 1 µL (500 U) peptide:N-glycosidase F (PNGase F; New England Biolabs, Inc., Beverly, MA) in 50 mmol/L sodium phosphate buffer (pH 7.5) containing 1% Nonidet P-40 at 37 C for 1 h.
Immunohistochemical staining of mammary glands
Immunohistochemical staining was performed as reported previously (17) with some modifications to detect rNIS proteins in the paraffin-embedded mammary gland sections (5 µm). Briefly, the tissue sections were incubated with rNIS polyclonal antibody pAb 716 at a 1:3000 dilution at room temperature for 1 h and then incubated with a 1:200 dilution of biotinylated goat antirabbit IgG (Vector Laboratories, Inc., Burlingame, CA) for 20 min.
Three-dimensional (3-D) histocultures
Specialized collagen gel manufactured from pigskin was purchased from Health Design Industries (Rochester, NY). The dehydrated collagen gel was presoaked in DMEM (Life Technologies, Inc., Gaithersburg, MD) with penicillin (10 units/mL) and streptomycin (10 µg/mL) at 37 C for 2 h and then divided into 12 pieces. At least 1 day before the start of the experiments, each piece was placed in 1 well of a 6-well tissue culture plate containing DMEM with 10% FBS (Life Technologies, Inc.), 0.1 mmol/L nonessential amino acids, and the antibiotics penicillin (10 U/mL) and streptomycin (10 µg/mL). Immediately after surgery or biopsy, human breast tumors in RPMI 1640 medium with penicillin/streptomycin were brought from the Ohio State University hospital tissue procurement to the laboratory. Fat and necrotic tissues were removed, and the remaining tissue was minced with double blades into approximately 1-mm3 pieces. About 10 of these tumor pieces were placed on each collagen surface. Medium (4 mL) with freshly added hormones was added and changed daily.
Ribonucleic acid (RNA) preparation and RT
Total RNA was extracted from frozen 3-D histocultured breast tumors using TRIzol reagent (Life Technologies, Inc.). The extracted RNA (1 µg) was reverse transcribed using random hexamer primers and Moloney murine leukemia virus reverse transcriptase (Life Technologies, Inc.) in a total volume of 20 µL, and the complementary DNA (cDNA; 1 µL) was used for real-time PCR amplification.
Real-time quantitative PCR
Real-time PCR is a novel technique that measures PCR
product accumulation during the exponential phases of PCR reaction. As
it allows you to monitor PCR product accumulation cycle by cycle, it
provides accurate measurement of target concentration over a wide range
of starting materials. Fluorescence-based real-time PCR was carried out
on a LightCycler (Roche, Mannheim, Germany) using two
independent single-labeled hybridization probes that hybridize
adjacently on the PCR product internal to the flanking PCR primers
(19). This method is based on the concept that a fluorescence signal is
generated if fluorescence response energy transfer (FRET) occurs
between two adjacent fluorophores (20). Human (h) NIS-F2 and hNIS-R8
primers (see Fig. 5
) were used to amplify the region between
nucleotides 681 and 1058 of the hNIS cDNA. The fluorescent probes were
designed as shown in Fig. 5. The 3'-labeled 19-mer fluorescein probe
(P1) was designed to anneal nucleotides 818–836 of the antisense
strand of hNIS cDNA; the fluorescein acts as a donor in FRET and also
blocks extension from the probe by Taq polymerase. The
acceptor (or detection) probe (P2) was 20-mer oligonucleotide, labeled
at the 5'-end with LightCycler-Red640 and modified at the 3'-end by
phosphorylation to block extension. This acceptor probe binds to the
antisense strand of the hNIS at nucleotides 840–859 with a distance of
4 bases 3' to the donor probe.
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Statistical analysis
Each value represents the mean ± SEM. Statistical evaluation of the results was performed with Student’s t test, and P < 0.05 was considered as significant.
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Results |
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As
99mTcO4-
is also known to be transported by NIS,
99mTcO4-
whole body scintigraphy was used to evaluate NIS activities in mammary
glands at different stages (Fig. 1A). In
virgin rats,
99mTcO4-
uptake activity was not detectable in the mammary gland, whereas it was
observed in the stomach, thyroid, and bladder (data not shown). In late
pregnancy (P-18d),
99mTcO4-
uptake activity in the mammary gland becomes visible by
99mTcO4-
whole body scintigraphy (Fig. 1A). In the lactating mammary gland at 1
day postdelivery (L-1d),
99mTcO4-
uptake activity was evident and was further increased in the lactating
mammary gland at 4 days postdelivery (L-4d). However,
99mTcO4-
uptake activity was decreased substantially in involuting mammary gland
when the pups were removed from dams for 42 h (I-42h).
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-count in
isolated tissues, revealed that RAIU in the mammary gland of virgin rat
was 2.3 ± 0.9-fold increased over that in spleen (as a control).
In the lactating mammary gland at 16 days postdelivery, RAIU was
35 ± 0.4-fold increased over that in spleen (Fig. 1B
). In the
involuting mammary gland, RAIU was only 5.47 ± 0.53-fold
increased over that in spleen (Fig. 1B). NIS expression is increased in lactating mammary gland
Western blot analysis indicates that two bands with molecular
masses of approximately 65 and 75 kDa were detected by an anti-rNIS
antibody in lactating rat mammary gland (Fig. 2A). The sizes of rNIS protein in mammary
gland were distinct from that of the rNIS protein in thyroid (
90
kDa). However, when the cell lysates of mammary gland and thyroid were
treated with PNGase F before Western blot analysis, the nonglycosylated
rNIS proteins detected in both mammary gland and thyroid had a
molecular mass of about 60 kDa. This suggests that rNIS glycoproteins
in mammary gland have a lesser degree of glycosylation than the rNIS
glycoproteins in thyroid. Furthermore, it appears that the expression
level of rNIS in lactating mammary gland was lower than that in thyroid
glands when an equal amount of total protein (100 µg/lane) was loaded
on SDS-PAGE (Fig. 2A). In agreement with RAIU found in rat mammary
glands of various stages (Fig. 1), rNIS protein is most abundant in
lactating mammary gland compared to mammary glands of virgin animals,
mammary glands during late pregnancy, and involuting mammary gland
(Fig. 2B). The finding that RAIU and rNIS expression were significantly
decreased in the involuting mammary gland indicates a quick turnover of
rNIS during the involution process.
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). When the primary anti-rNIS antibody
was substituted with a rabbit IgG, no immunostaining was observed in
the mammary glands investigated (data not shown). RAIU in lactating mammary gland is decreased by treatment with an OTA or Br-CT
To investigate whether OT or PRL hormone has any regulatory effect
on RAIU in lactating mammary gland, lactating rats were treated with
either a selective OTA, des
Gly-NH2,d(CH2)5[D-Tyr2,Thr4]OVT
(15), or Br-CT, an inhibitor of PRL release. RAIU in lactating mammary
gland was decreased 53 ± 8.1% (P < 0.05) in the
Br-CT-treated rats and was decreased 42 ± 2.3%
(P < 0.05) in OTA-treated rats compared to that in
saline-injected rats (Fig. 3A). In
contrast, RAIU in thyroid (Fig. 3B) and stomach (Fig. 3C) were not
affected by Br-CT and OTA treatment, indicating that the effects of
Br-CT and OTA were mammary gland specific. However, when the animals
were treated with both Br-CT and OTA, no additive effect was observed
on RAIU reduction (33 ± 17.8%; P = 0.15)
compared to that in Br-CT- or OTA-treated rats. Although iodide
organification rates in thyroid (Fig. 3E) and stomach (Fig. 3F) were
not significantly different among different experimental groups, iodide
organification rates in lactating mammary glands were decreased in
Br-CT-treated animals (38.8 ± 15.5%; P = 0.072)
and OTA-treated animals (44.0 ± 4.43%; P =
0.038), but not significantly in Br-CT- plus OTA-treated animals
(30.4 ± 12.0%; P = 0.104; Fig. 3D), compared to
those in saline-injected rats. It is noteworthy that the pups were
still suckling in all animals studied, and that serum PRL levels were
greatly reduced in animals treated with Br-CT or Br-CT plus OTA (see
Fig. 4).
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To investigate whether OT or hPRL has any direct effect on hNIS
expression in human breast tumors, we examined the mRNA level of hNIS
in 3-D histocultures of tumor tissues treated with OT or hPRL by
real-time quantitative PCR analysis. Forty cycles of amplification were
performed with cDNA of each sample, a negative control (no template)
and serially diluted hNIS/PcDNA3 plasmid DNA standards, using the FRET
detection system (Fig. 5A). Figure 5B
shows fluorescence data for the diluted hNIS/PcDNA3 plasmid DNA
standards generated by the LightCycler instrument. No increase in
fluorescence signal was observed in the absence of template (Fig. 5B, curve E). The mRNA levels of hNIS were increased in a dose-dependent
manner by OT in three of four samples investigated, and by hPRL in two
of two samples studied (Fig. 6, A and B).
However, the combination of OT and hPRL did not have an additive effect
on hNIS expression in the 3-D histocultured breast tumor (Fig. 6B).
Instead, the increases in hNIS mRNA were lower than those in OT- or
hPRL-treated samples.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RAIU activity analyzed by either
99mTcO4-
whole body scintigraphy or
125I- -count was
maximal in the mammary glands of lactating rats, followed by mammary
glands at 42 h involution, and then by mammary glands from
pregnant/virgin rats. This result is in agreement with the in
vitro 131I- -count
study reported by Maqsood and Peineke (21). In our study we further
showed that NIS expression is most abundant in lactating mammary gland.
Interestingly, although RAIU activity can be detected in
vivo in the mammary gland of pregnant rat and involuting mammary
gland, Western blot analysis was not sensitive enough to detect NIS
expression in the mammary gland of pregnant rat or involuting mammary
gland.
We showed that rNIS was mainly detected in the basolateral membrane of alveolar cells and small ductal epithelial cells of lactating rat mammary gland. This finding suggests that iodide is transported from blood to alveolar cells and small ductal cells and then moves to the lumen, where the milk is accumulated and secreted in the mammary gland. In contrast, hNIS was detected in ductal cells, but not in acinar cells, of the human salivary gland (17), suggesting that iodide is added to the saliva in the ductal cells of salivary gland.
The release of PRL was effectively inhibited by Br-CT treatment. Therefore, the modest inhibitory effect of Br-CT on RAIU in lactating mammary gland is not due to suboptimal inhibition of PRL release. However, it is not known whether the effects of oxytocin on NIS expression are fully blocked by OTA treatment, even though a previous study that used similar OTA dosage demonstrated an inhibitory effect on uterine contraction (15). It is possible that the modest inhibitory effect of OTA on RAIU in lactating mammary gland is due to suboptimal inhibition of OT. Furthermore, the inhibitory effects of OTA and Br-CT on RAIU could be masked by a possible long half-life of NIS protein in lactating mammary glands. Finally, it is possible that NIS expression in mammary glands is also modulated by other factors yet to be identified. In any event, our study showed that RAIU in lactating mammary gland is modulated at least in part by OT and PRL.
It has been reported that PRL stimulates iodide accumulation in
cultured mammary gland from the midpregnant mouse (22). In this study
we showed that PRL increases hNIS mRNA level in a dose-dependent manner
in two human breast tumor investigated. It has been shown that the
expression levels of genes containing GAS (-interferon activation
sequence, TTCNNNGAA) are increased by PRL-PRLR signal transduction
pathways through the activation of Jak2/Stat5 cascades in breast cells
(23). Interestingly, a GAS was identified in the promoter region of
hNIS -2880 to -2871 upstream from ATG translational start site
(GenBank/EMBL no. AJ132551 and AJ224353).
We have shown that OT increases hNIS mRNA levels in three of four human breast tumors investigated. Interestingly, OTR has been reported to be expressed in 50–90% of the breast cancers derived from glandular or ductal epithelium (12, 13, 14). OTR is a G protein-coupled receptor that can activate the Gs-cAMP-protein kinase A (PKA) pathway and/or the Gq/11-(inositol-1, 4, 5-triphosphate-Ca2+)/(diacylglycerol)-protein kinase C (PKC) pathway, depending on ligands and cell types (24). As the stimulation of NIS expression by TSH in thyroid cells is mainly mediated by the Gs-cAMP-PKA pathway, OT may also stimulate hNIS expression in breast tumors by activating the Gs-cAMP-PKA pathway.
Although OT or PRL alone did increase hNIS mRNA levels in some human breast tumors, the combination of OT and PRL seems to have an antagonistic effect on the increase in hNIS mRNA levels. These data indicate that the signaling pathways activated by OT/OTR and PRL/PRLR that stimulate NIS expression in mammary gland may interfere with each other. Indeed, it has been reported that Jak/Stat signaling pathways are inhibited by PKA (25, 26) and PKC (27, 28). It is also possible that OT and/or PRL may stimulate other factors in the breast that, in turn, affect NIS expression. A thorough understanding of the hormonal regulation of NIS expression in breast tissue is required before an optimal regimen of hormonal stimulation of hNIS expression can be developed to explore the possibility of radioiodide therapy in patients with breast cancer.
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Acknowledgments |
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Footnotes |
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Received February 2, 2000.
Revised April 13, 2000.
Accepted April 19, 2000.
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