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Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104-4283
Address all correspondence and requests for reprints to: Carol Reynolds, M.D., Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, 3400 Spruce Street, 6 Founders Pavilion, Philadelphia, Pennsylvania 19104-4283.
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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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The quantitation of growth factor receptors, such as those for estrogen, progesterone, and her2-neu, has been of significant utility in the prognostication of the biological behavior of human breast cancer (8, 9). In addition, the presence of these receptors in such malignancies has provided the basis for established (i.e. tamoxifen) as well as evolving endocrine therapies, (anti-her2-neu) (10) directed against breast cancer. Thus, the quantitation of both the PRLr and its locally expressed ligand could be of prognostic or therapeutic significance. Prior RIA-based studies have detected specific receptor-based binding of PRL in only 20–60% of human breast tissues (11, 12, 13, 14). Many but not all of these studies observed a weak association between the expression of the PRLr and estrogen receptor-progesterone receptor (ER-PR). The variability among these studies was most likely due to the difficulties inherent in the biochemical quantitation of PRLr. Thus, secondary to the high affinity of the PRLr for its ligand, biochemical techniques were used that may have resulted in the denaturation of radioligand or loss of receptor during preparation, resulting in the interlaboratory variability in PRLr quantitation (11, 13).
Data from our laboratory (15) and others (16, 17) have indicated that the expression of PRL and the PRLr occurs in many breast cancers at the RNA level when assessed by reverse transcriptase-PCR (RT-PCR). Additional recent studies have also indicated that the use of anti-PRL reagents can block the in vitro growth of human breast cancer cell lines (17, 18). Taken together, these results suggest that PRL functions as an autocrine/paracrine growth factor within breast tissues, possibly contributing to the pathogenesis of breast cancers. Therefore, to test this hypothesis, the presence of both PRL and PRLr in human breast tissues was examined. To avoid the difficulties inherent in previously used RIA-based techniques, the expression of PRLr in primary breast carcinoma was examined using an immunohistochemical (IHC) technique, whereas the expression of PRL was detected by in situ hybridization. These findings were subsequently correlated with the expression of the ER-PR complexes noted in parallel sections. The results obtained here confirm prior RT-PCR-based studies and demonstrate the widespread expression of both PRL and the PRLr in normal and malignant human breast epithelium.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In situ hybridization for PRL was performed using the methodology described by Montone et al. (19). Briefly, formalin-fixed paraffin-embedded breast tissues were sectioned, deparaffinized, and rehydrated using the standard technique. The sections were digested with 0.5 mg/ml pepsin (stock solution, 2.5 mg/ml pepsin diluted in 0.12 N HCl enzyme buffer) for 3 min at 105 C. Hybridization was performed with 250 ng/ml biotinylated probe, antisense and sense (5'-GCAGTTGTTGTTGTGGATGATTCGGCA-3' and 5' TGTCCCGCCGGGGCTTCCCGATGCCAG-3'), for 3 h at 45 C and was detected by a streptavidin-biotin-horseradish peroxidase complex with diaminobenzidine as a chromogen and hematoxylin as a counterstain.
IHC analysis of the PRLr used a streptavidin-horseradish-immunoperoxidase method in conjunction with the automated capillary gap technology (BioTek Solutions) (20). Formalin-fixed paraffin-embedded breast tissues were sectioned, deparaffinized, and labeled with 6.6 ng/ml of the U6 anti-PRLr monoclonal antibody or appropriate isotype-matched control antibody for 50 min. This U6 antibody recognizes an epitope on the extracellular domain of the PRLr and, as such, recognizes all known isoforms of the PRLr (21). Antigen-antibody complexes were detected by a biotinylated antimouse secondary antibody and a streptavidin-biotin-horseradish peroxidase complex, with diaminobenzidine as a chromogen and hematoxylin as a counterstain. IHC staining for vimentin (Dako Corp., Carpenteria, CA; 1:20 dilution) was performed on all PRLr-negative tumors to assess the preservation of the antigen.
The expression of PRL-PRLr by in situ hybridization or IHC staining was graded for both the extent and intensity of label. The extent of staining was evaluated on a scale of 0–4 (0 = 0%; 1 = 1–2%; 2 = 3–10%; 3 = 11–50%; 4 = >50%) for each of the following components: infiltrating carcinoma, in situ carcinoma, and benign lobules/ducts. To determine the percentage of positive staining, a maximum of 300 cells and a minimum of 100 cells were counted. At least 3 lobular units or ducts were required for score generation. Blood vessels were considered positive in this evaluation if either the endothelial or smooth muscle components demonstrated label. Only vessels inside or within 1 high power field of the tumor were examined in this study; both large and small caliber vessels were evaluated. The breast stroma both within and outside the tumor was evaluated. Cellular staining was scored independently by two observers (C.R. and C.M.P. for the IHC analysis and C.R. and K.T.M. for the in situ hybridization). There was no disagreement regarding the presence or absence of staining in any case between the observers. Any disagreements in the extent of staining were resolved after joint microscopic review. A general assessment of overall labeling intensity was also qualitatively made for each tissue compartment on a 1–3+ scale.
Quantitation of ER-PR was performed using biochemical and IHC methods. Biochemical analysis was performed on fresh tissue using the modified dextran-coated charcoal (DCC) assay (22, 23). IHC analysis was performed on frozen or paraffin-embedded breast tissue. Preliminary fixation used the Abbott Laboratories protocol for preparation of tissue specimens before the immunocytochemical staining procedure (24). Briefly, frozen breast tissues were sectioned and stored in a sucrose/glycerol solution. Once removed from solution, they were placed in 3.7% formaldehyde-PBS, sequentially rinsed first with cold methanol then with cold acetone, and rinsed in PBS at room temperature. Formalin-fixed paraffin-embedded breast tissues were sectioned, deparaffinized, and rehydrated using the standard technique. The paraffin-embedded tissues for ER detection were treated with pronase digestion (0.25 mg/10 ml PBS) before the blocking procedure. Frozen or paraffin-embedded breast tissue slides were then processed for IHC on an automated immunostainer (BioTek Solutions, Ventana BioTek Systems, Tucson, AZ) (20). All slides were incubated with nonimmune goat blocking serum, washed with PBS, and then incubated at room temperature with the primary antibody (PgR-ICA Monoclonal and ER-ICA Monoclonal, according to the kit instruction booklet, Abbott Laboratories, North Chicago, IL) for 16 h in a humid chamber. After incubation with the primary antibody, the slides were washed, and antigen-antibody complexes were detected by a biotinylated secondary antibody (universal secondary, BioTek Solutions) and an avidin-biotin complex with diaminobenzidine as a chromogen and hematoxylin as a counterstain.
DCC results for ER were positive when values were equal to or greater than 10 fmol/mg protein, and those for PR were positive when values were equal to or greater than 20 fmol/mg protein. IHC results were evaluated for nuclear staining immunoreactivity for ER and PR without knowledge of the corresponding DCC result. In this study, IHC results were scored positive for ER and PR if immunoreactivity showed greater than 5% nuclear staining.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The expression of PRL and PRLr in human breast tissues was examined by
in situ hybridization and IHC analysis, respectively.
Qualitatively, intense (3+) labeling for both PRL and PRLr was observed
within in situ and invasive components of malignant
epithelium (Fig. 1
); a similar labeling
intensity was also observed over benign ducts and lobules. The label
for PRL messenger RNA was noted diffusely throughout the cytoplasm of
benign and malignant breast epithelial cells. Expression of the PRLr
protein occurred throughout the cytoplasm and was observed at both the
basal and apical cell membranes. Semiquantitatively, there was
widespread expression of PRL and PRLr in malignant and adjacent normal
breast epithelium (Fig. 2), with the vast
majority of the cases revealing extensive labeling of the epithelial
cells (>50%). Within malignant epithelium (either infiltrating or
in situ components), a complete absence of PRL expression
was observed in only 4% of the cases, whereas a loss of PRLr
expression was observed in 5%. Similarly, few normal tissues
demonstrated a complete absence of either ligand or receptor (3% PRL
negative and 7% PRLr negative).
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); only 3% of the
cases demonstrated a complete absence of the anti-PRLr label. In
contrast, 80% of the intratumoral stroma demonstrated a complete lack
of PRLr expression. Expression of PRL within the stroma was seen in
only two cases (3%), with one case demonstrating intratumoral stromal
positivity, and the other extratumoral showing positivity. Similarly,
intratumoral blood vessels revealed the presence of PRLr expression
more frequently than PRL (26% PRL positive and 90% PRLr
positive).
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). No clear-cut association between
steroid receptor status and the expression of PRL or PRLr (Table 1) was noted. Preservation of
antigenicity within the few PRLr-negative tumors was confirmed in all
cases by secondary staining with antivimentin antibodies. Of the small
number of tumors that were PRL negative (3%) or PRLr negative (6%);
(Table 2), no one tumor feature
(i.e. morphology or ER-PR status) could be unequivocally
associated with the lack of PRL or PRLr expression.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Given these initial data, this study sought to evaluate the levels of PRL and PRLr expression within normal and malignant human breast tissues using modern and sensitive histological techniques. Past RIA-based studies, conducted in the late 1970s and early 1980s, found variable levels of PRLr expression in 20–60% of breast carcinomas and did not evaluate local PRL expression (11, 12, 13, 14). Given these acknowledged difficulties in detecting PRLr by RIA, our laboratory chose to use histological approaches. The data obtained by these approaches indicate that PRLr expression occurs in the vast majority of breast carcinomas. The extent and intensity of PRLr expression were equivalent in both the infiltrating and in situ components of the carcinomas examined. Sixty to 80% of the cases showed an extent of staining greater than 50% within the malignant mammary epithelium. The extent and intensity of PRLr expression were approximately equivalent in both malignant and benign breast epithelium. These findings demonstrate that the expression of PRLr is far more widespread in breast epithelium than previously quantitated by RIA and support previous data obtained by Shiu et al. (7) that demonstrated high levels of PRLr expression (2,000–10,000 receptors/cell) in 11 of 11 ER-positive and ER-negative breast cancer cell lines. The improved detection of PRLr in mammary epithelium seen here may be the result of a relative lack of antigen denaturation, improved sensitivity, and the ability to detect receptor expression on a per cell basis, advantages inherent in the IHC technique used.
The data presented here also revealed a diffuse localization of the PRLr on both the apical and basal aspects of benign and malignant breast epithelial cells. From a teleological prospective, such a dual localization of receptor would make little sense if the PRLr was engaging ligand only obtained from endocrine sources. Thus, if ligand was only presenting itself from the bloodstream, one would anticipate a distribution of PRLr limited to the basal aspect of the epithelial cell. Instead, the histological localization of PRLr demonstrated here supports the hypothesis (16) that PRL is used in an autocrine/paracrine manner. The diffuse cell surface localization of PRLr throughout the mammary epithelial cell, therefore, may provide an optimal distribution required for the interaction of receptor with ligand obtained from the blood, milk, or adjacent epithelial cells.
The expression of PRL in breast tissues has been examined by previous studies, largely through the use of RT-PCR (15, 16). Although this technique is indisputably sensitive, it has not provided a determination of PRL expression on an individual cell basis within the breast. Although the detection of ligand at the protein level would be desirable and has been demonstrated in vitro on breast cancer cell lines (15, 17), the previously documented uptake of PRL by PRL-responsive tissues (30, 31) required an assessment of ligand expression at the RNA level by in situ hybridization. The current application of this technique found extensive and intense expression of PRL in the vast majority of benign and malignant breast epithelium (>90%). Appreciably lower levels of PRL messenger RNA were observed in the stroma and endothelium (in both intensity and extent of label); thus, the predominant source for PRL within the breast appears to be of epithelial origin. With respect to the composition of milk, this finding is of significance, as the appreciable quantities of PRL in this fluid have been attributed to the transcytosis of endocrine-derived PRL across the mammary epithelial cell. These data raise the plausible alternative that the PRL found within milk is synthesized and secreted locally by the mammary epithelial cells. With respect to neonatal health, these findings are significant given the ready transport of PRL across the fetal gut (32, 33) and its role as an immunostimulatory factor necessary for the interleukin-2-driven expansion of T lymphocytes and the inhibition of glucocorticoid-induced apoptosis of lymphocyte progenitors.
Not all mammary carcinomas examined demonstrated expression of the PRLr
or its ligand. An association between these few cases of
PRL-PRLr-negative breast carcinomas and ER-PR status was not detected.
Although the basis for this loss of expression cannot be evaluated by
these studies, direct mutation to the PRL-PRLr locus may have occurred.
Alternatively, down-regulation of the PRL-PRLr locus may have resulted
from direct mutations in the transcription factors or the upstream
activation machinery, which are necessary for
trans-activation of the PRL-PRLr loci. The distal PRL
promoter, used by nonpituitary tissues, contains several known binding
sites for transcription factors, including seven PR-binding half-sites,
two Pit-1-binding sites, two TEF-1 sites, 12 C/EBP
sites, and one
half-site for cAMP response element-binding protein (34, 35).
Interestingly, both Pit-1 and PR appear not to exert direct
transcriptional control at this site in endometrial cells. In contrast,
stimulation of endometrial cells with cAMP robustly
trans-activates the PRL promoter. Whether such
trans-activation is driven by the endogenous cAMP response
element-binding protein site and whether similar mechanisms are used in
human breast tissues should provide fertile ground for future
research.
In general, most breast tissues did not demonstrate appreciable expression of PRL within the stromal or vascular compartments. An appreciable drop in the extent of PRLr expression was noted when comparing the extra- and intratumoral stromal compartments. This drop in the overall extent of intratumor stromal PRLr expression may result from autocrine elaboration of PRL by adjacent malignant epithelium, resulting in a subsequent down-regulation of the PRLr. Extensive expression of the PRLr was noted within the endothelium and smooth muscle of intratumoral blood vessels. Recent data revealed that the 16-kDa N-terminal fragment of human PRL is a potent regulator of angiogenesis (36, 37), an essential component of tumor growth. Thus, expression of the PRLr by endothelial tissues may serve to regulate the growth of vascular tissues within the breast.
These data demonstrate for the first time that, unlike ER-PR and her2-neu, the PRL-PRLr complex can be found in the vast majority of human breast cancers, with no correlation to ER-PR status or histological type. Taken together, these findings suggest a negligible utility in the future quantitation of this complex in the prognostication of the biological potential of human breast carcinoma. When coupled with recent data that demonstrate the effective in vitro inhibition of the proliferation of breast cancer cell lines when treated with PRL antagonists (18), these findings suggest that therapies directed at the PRLr complex may have considerable clinical utility in many, if not most, human breast cancers. Based on the current findings, effective therapy directed against the PRL-PRLr complex must block incoming signals from both endocrine and autocrine/paracrine levels. Whether such therapy will use anti-PRLr monoclonal antibodies (17), mutant PRL antagonists (18), or inhibitors of PRLr signaling (37) awaits further data from appropriately designed in vivo studies.
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Acknowledgments |
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Footnotes |
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Received May 9, 1997.
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