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Tumor Biology |
McGill Centre for Translational Research in Cancer, Lady Davis Institute for Medical Research and Departments of Medicine, Pathology, Oncology, and Pharmacology and Therapeutics, Sir Mortimer B. Davis Jewish General Hospital, Faculty of Medicine, McGill University, Montreal, Quebec, Canada H3T 1E2 [D. W. L., G. B., L. A., H. T. H., G. D. C., M. A. A-J.]; and Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada N6A 5C1 [D. W. L., P. F.]
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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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Breast tumor intercellular interactions within the tissue microenvironment play an important role in this multistage carcinogenic process. In normal conditions, the mammary gland is composed of several cell types that interact with each other and with other components of the tissue microenvironment, including neighboring mesenchymal cells and the extracellular matrix. These cell-cell interactions involve physical and dynamic organization mediated by distant signals through secreted growth factors and signaling molecules as well as direct junctions. The latter include tight junctions mediated by proteins such as occludin and zonula occludins (reviewed in Ref. 1 ), gap junctions (reviewed in Ref. 2 ), adherence junctions mediated by cadherins (reviewed in Ref. 3 ), and desmosomes (reviewed in Ref. 4 ). Many of these junctions are interdependent and probably are regulated through a coordinated process (5) . Alteration of GJIC3 is among the early changes associated with carcinogenesis and restoration of gap junctions can suppress tumor cell growth (6, 7, 8, 9, 10, 11) . Furthermore, phorbol esters and epidermal growth factor activation of protein kinases down-regulate GJIC (12, 13, 14, 15, 16) . GJIC has been implicated in many biological functions, including the regulation of cell growth and differentiation (reviewed in Ref. 17 ).
GJIC mediates the transfer of ions, nucleotides, and small regulatory molecules from cytoplasm to cytoplasm without leakage into the extracellular space (6 , 18) . Gap junctions are composed of multiple hemichannels (connexons) in the plasma membrane of one cell joined in mirror symmetry with the same number of hemichannels in the apposing cell membrane. Connexons are formed from members of a multigene family of distinct but functionally related proteins called Cxs (19 , 20) . In the course of gap junction assembly, individual channels cluster at the cell surface to form gap junction plaques (2) . Gap junctions are dynamic structures with relatively short half-lives of 1–5 h (2 , 21) . They are tightly regulated by voltage, growth factors, a number of secondary messengers including cAMP (15 , 22, 23, 24) , and retinoids (25) and are subjected to phosphorylation by a number of protein kinases (16 , 20 , 26) .
Presently, 15 Cx genes have been identified in mammalian cells (27 , 28) . Three Cxs have been detected in normal breast tissue, namely Cx43, Cx26, and Cx32. Cx43 is the predominant Cx in human breast epithelium, and it was detected predominantly between myoepithelial cells (29) . There is evidence suggesting that Cxs may play a role in normal mammogenesis, lactogenesis, and involution. It has been shown that Cx26 levels in the epithelium increase substantially in the lactating mouse mammary gland epithelium and decline during involution (30) , and hormones such as estrogens and progesterones have been shown to regulate the expression of the Cx43 gene (31) .
Here, we examined the expression of Cx43-mediated gap junctions in a panel of human breast cancer tissues and their matched normal controls. Results were compared to those from human breast cancer cell lines and experimental murine mammary carcinomas.
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MATERIALS AND METHODS |
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summarizes clinical information of human breast tissues studied. Of the 32 tumor tissues studied, 4 cases were DCIS, 21 were IDC, and 7 were ILC. Control normal tissues, derived from normal breast surrounding primary tumors from the same patient, were available for study in 14 cases. Tissues were fixed in buffered formalin and embedded in paraffin. Five-µm sections were prepared for analysis of various markers by immunohistochemistry or confocal microscopy. Parallel sections were stained with H&E for morphological examination.
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75% of animals by day 90 following carcinogen administration. On day 105 after DMBA treatment, rats bearing tumors were sacrificed by CO2 exposure, and mammary tumors were harvested, quickly frozen in liquid nitrogen, and stored at -80°C for later analysis. Normal mammary tissues were derived from rats treated with the vehicle alone and prepared as described for mammary tumor tissues.
Cell Lines and Cell Culture.
The cell lines used in this study consisted of human breast carcinoma cell lines Hs578T, MDA-231, MDA-468, HBL-100, T47-D, and ZR-75. All these cell lines were obtained from the American Type Culture Collection (Manassas, VA). Cells were maintained as monolayer cultures in 
-MEM supplemented with 10% FCS (Life Technologies, Inc., Grand Island, NY). Confluent stock cultures were trypsinized and plated at 1 x 106 cells per 75-cm2 plate in -MEM supplemented with 10% FCS. After 24 h, the cell monolayer was rinsed once with serum-free -MEM and then incubated for a further 48 h in -MEM containing 2.5% FCS.
Immunofluorescent Labeling and Confocal Microscopy.
Deparaffinized sections were blocked with BSA and immunolabeled for 1 h with 5–8 µg/ml affinity-purified anti-Cx43 antibody as described in Laird et al. (32)
. Sections were washed and immunolabeled with antirabbit IgG conjugated to Texas Red for 1 h. For double-labeled experiments, sections were first labeled for Cx43, as described above, followed by a mouse anticytokeratin antibody (1:25 dilution; Boehringer Mannheim, Laval, Quebec, Canada) and antimouse IgG conjugated to fluorescein. Immunofluorescent labeled tissue sections were analyzed using the Zeiss LSM 410 inverted confocal microscope as described in Laird et al. (32)
. Briefly, to excite and detect Texas Red, an argon/krypton mix gas laser that emits a 568-nm line was used, and the resulting fluorescence was passed through a 590 nm long pass filter. The same laser was used to emit a 488 nm line to excite fluorescein, and the resulting fluorescence was collected after passing through a 515–565-nm band pass filter. All fluorescent signals were collected on a photomultiplier and stored as digital images. Composite images were printed on a Tektronix color printer. Normal and tumor breast tissue was examined and scored based on the presence of gap junction plaques. In many cases, both normal and tumor tissue were present on the same slide.
Immunohistochemistry Analysis.
Immunohistochemical analysis was performed on deparaffinized slides using the automated Ventana immunostaining machine (Ventana Medical Systems Inc., Tucson, AZ). This system is based on localization of bound antibodies by a biotin-conjugated secondary antibody in conjunction with an avidin/streptavidin-enzyme conjugate. A mouse monoclonal antibody directed against an epitope on human ER (clone 6F11; Ventana Medical Systems) and a mouse antibody directed against an epitope on human PGR (clone PGP-1A6; Ventana Medical Systems) were used to examine the levels of ER and PGR expression, respectively. The anti-erbB-2 Ab4 antibody (Oncogene Science, Cambridge, MA) was used at a dilution of 1:100, whereas ER and PGR antibodies were used undiluted. Normal goat serum was used to block the nonspecific binding sites prior to incubating the sections with primary antibodies in a humidified chamber for 18 h at 4°C. Antibody binding was visualized by subsequent incubations with biotinylated secondary antibody and an avidin-biotin-horseradish peroxidase complex, followed by a 4-min incubation in diamine tetrahydrochloride before counterstaining with hematoxylin. Scoring of sections was carried out blinded to clinical characteristics. Specimens were assigned one of the five staining scores, as follows: +++, heavy staining on 75–100% of the cells; ++, moderate staining on 25–75% of the cells; +, focally positive on 5–25% of the cells; -/+, weak staining on <5% of the cells; or -, negative staining. For ER and PGR, the tumors were considered positive if staining is was found in >5% of the cells.
Northern Blot Analysis.
Fresh tissues, frozen immediately in liquid nitrogen after surgery, were used to extract total RNA. Cells were collected at 70% confluence. Total RNA was isolated using the RNAZol B premixed solution (Tel-Test, Friendswood, TX). RNA integrity was examined by agarose-formaldehyde gel electrophoresis. Twenty µg of RNA were electrophoresed through a 1% formaldehyde-agarose gel and blotted onto nitrocellulose membrane for 18 h. Filters were prehybridized for 2 h at 42°C in prehybridization buffer [containing 50% (v/v) formamide, 5x SSC, 5x Denhardt’s solution, 250 µg/ml sonicated calf thymus DNA, and 0.5% SDS]. Cx43 cDNA was labeled with [32P]dCTP (1 x 106 cpm/ml) using an oligolabeling kit (Pharmacia) and was then added to the blots. Hybridization was carried out for 20 h at 42°C in hybridization buffer [dextran sulfate:prehybridization buffer, 1:4 (v/v)]. Membranes were washed three times for 10 min at room temperature in 1x SSC containing 0.1% SDS and three times at 60°C for 10 min in 0.1x SSC containing 0.1% SDS, and then they were subjected to autoradiography. After development, X-ray films were scanned with a spectrophotometer equipped with LKB Ultrascan Laser Densitometer. After each probing, filters were stripped of probes by three washes in 0.1x SSC and 0.1% SDS at 100°C for 15 min and exposed to X-ray film to ensure that the probe was completely removed. The stripped nitrocellulose membranes were reprobed with mouse GAPDH cDNAs, used to normalize for mRNA levels.
Western Blot Analysis.
Cells were grown in serum supplemented medium until they were 70% confluent in 75-cm2 flasks. Cells were washed twice in cold PBS and then lysed directly using lysis buffer [1% Triton X-100, 10 mM Tris-HCl (pH 8.0), 60 mM KCl, 1 mM EDTA, 1 mM DTT, 0.5% NP40, 0.5 mM phenylmethylsulfonyl fluoride, 0.01 mg/ml leupeptin, 0.01 mg/ml pepstatin, 0.01 mg/ml aprotonin, and 5 mM sodium orthovanadate]. The lysate was incubated for 10–15 min at 4°C and centrifuged at 14,000 x g at 4°C for 15 min. The supernatant was used to determine protein concentration. Cell extracts were resolved by 10% SDS-PAGE, transferred to nitrocellulose (Costar, Cambridge, MA), blocked in 5% milk in PBS, and then incubated with an anti-Cx43 rabbit polyclonal antibody (21)
. Immune complexes were detected by horseradish peroxidase conjugates using the enhanced chemiluminescence detection reagents (Amersham). Blots were subsequently stripped in 100 mM 2-mercaptoethanol, 2% SDS, and 62.5 mM Tris-HCl (pH 6.7) at 50°C for 30 min and then immunoblotted with monoclonal anti-GAPDH (clone 6C5; Cedarlane Laboratories, Hornby, Ontario, Canada).
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RESULTS |
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show clear morphological changes between normal and cancer tissue. The punctate Cx43 immunostaining pattern seen in normal tissue (Fig. 1B
, inset, arrows) was lost in IDC (Fig. 1D)
, ILC (Fig. 1F)
, and mixed DCIS/IDC (Fig. 1H)
. Fig. 1 (A–D)
shows different regions of the same tissue section, and fluorescent images (Fig. 1, B and D)
were collected under identical imaging conditions.
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and an invasive ductal carcinoma (Fig. 2, D–F)
taken from different regions of the same breast were immunofluorescently double-labeled for Cx43 and an intermediate filament protein, cytokeratin. Punctate Cx43 immunolabeling was seen in normal (Fig. 2, A and C)
but not tumor (Fig. 2, D and F)
tissue. Cytokeratin labeling, which is used as a marker for cells of epithelial origin, was seen in both normal (Fig. 2, B and C)
and tumor (Fig. 2, E and F)
tissue, confirming the epithelial phenotype of the breast carcinoma.
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summarizes the expression of Cx43 gap junctions in all human breast tissues tested. In all cancer tissues, regardless of their grade, distinct Cx43 gap junctions were undetectable, although they were always present, at various levels, in normal tissues. It is plausible that some of these tumors were expressing a low level of Cx43, but the Cx43 was clearly not assembled into classical gap junctions. The expression of Cx43 gap junctions in normal tissue varies from moderate to high expression. To examine whether the absence of Cx43 gap junctions is correlated with the expression of ER, PGR, and/or erbB-2 tyrosine kinase receptor, we immunostained tissue sections from the same paraffin blocks to evaluate the presence of these three common prognostic markers associated with breast cancer. No correlation between Cx43 gap junctions and ER, PGR, and/or erbB-2 status was found in the breast tissues used (Table 1)
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To confirm and further examine Cx43 gap junction expression in breast cancer, we performed both Northern and Western blots on a panel of human breast cancer cell lines. As indicated in Fig. 3
, both Cx43 protein and mRNA were significantly down-regulated in all breast cancer cells lines except Hs578T and MDA-231. This lack, or low level, of Cx43 mRNA expression in MDA-468, HBL-100, T47-D, and ZR-75 cells was not due to gross gene rearrangement as measured by Southern blot analysis (data not shown).
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, both Cx43 mRNA and protein are barely detectable in cancer tissues, but they are highly expressed in normal rat mammary tissues.
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DISCUSSION |
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This study demonstrates that down-regulation of Cx43 gap junctions, which is expressed in normal breast epithelium, is a common feature of breast cancer. Cx43 gap junction down-regulation was observed in tissue at various stages of tumorigenesis, including DCIS, invasive IDC, and ILC, supporting earlier studies that suggested that the loss of Cx43 is an early event in carcinogenesis (reviewed in Ref. 17 ). Furthermore, data obtained with rat mammary carcinoma induced by DMBA also demonstrate that the loss of Cx43 gap junctions is a common feature of mammary neoplastic transformation. Down-regulation of Cxs has been reported in other tumor cells, including prostate (7) , liver (36) , and lung carcinomas.4
Consistent with our study, Wilgenbus et al. (37)
failed to identify Cx43 in the parenchymal components of the seven breast tumors they examined. However, Jamieson et al. (38)
found mainly heterogeneous cytoplasmic Cx43 immunostaining in carcinoma cells of 50% of the tumors examined, and in some cases, Cx43 was organized into what appeared to be gap junctions. In our studies, the samples were scored based on the presence of assembled gap junctions and not on the possibility that the carcinoma cells may express low levels of unassembled Cx43 in the cytoplasm. In essence, if some human breast tumors express Cx43 in vivo but fail to assemble gap junctions, these tumors would not be capable of Cx43-mediated cell-cell communication. It is possible that the defect in some breast tumor cells is their inability to traffic and assemble Cx43 into gap junctions at the cell surface. Together, these studies suggest that the majority of breast carcinoma cells are unlikely to communicate via Cx43 gap junctions. Although Cx26 has been demonstrated to be a minor Cx in normal human breasts, a study by Jamieson et al. (38)
provided evidence that it might be up-regulated in some breast tumors. However, similar to Cx43, the immunostaining of Cx26 was mostly cytoplasmic. Jamieson et al. (38)
suggested that tumor cells may not be communicating via Cx26 gap junctions. Nevertheless, in future studies, it will be important to examine the regulation of Cx26 in breast carcinomas.
There are several markers associated with breast cancer progression and/or poor prognosis, including loss of heterozygosity at specific loci, loss of ERs, overexpression of specific member of the erbB tyrosine kinase receptors, and p53 mutations (reviewed in Refs. 39, 40, 41 ). In our study, the absence of Cx43 gap junctions was observed in breast cancer tissues, regardless of their ER, PGR, or erbB-2 status, suggesting that Cx43 may be an independent marker for breast carcinogenesis. A recent study suggested that the loss of p53 function occurs at early stages of breast cancer progression, whereas overexpression of ras may be a late-stage event (42) . On the basis of our study of precursors for invasive breast cancer, Cx43 regulation may occur at an early stage because Cx43 gap junctions were not observed in the DCIS samples examined. Jamieson et al. (38) reported Cx43 immunostaining in the myoepithelium of four DCIS tumors, but no staining of the carcinoma cells themselves was observed. However, additional screening of a large panel of DCIS is required to draw a final conclusion. The lack of any correlation between ER, erbB-2, PGR, and Cx43, however, does not rule out a possible interaction between these signaling pathways. Indeed, overexpression of erbB-2 as well as several growth factors, including epidermal growth factor, has been reported to regulate Cx43 expression (43 , 44) . Hormonal regulation of GJIC has been demonstrated in numerous studies (45, 46, 47, 48) . In myometrium, estrogen up-regulates the expression of Cx43 mRNA, whereas progesterone antagonizes this increase (45 , 46) . Examination of the upstream noncoding region of Cx43 has revealed putative estrogen responsive elements (46) . Estrogens induce transcriptional up-regulation of Cx43 (31 , 48) but down-regulate erbB2 mRNA and protein and inhibit erbB-2 transcription in ER-positive breast tumor cells (49 , 50) , suggesting possible cross-talk among these regulatory pathways.
Although the molecular mechanisms by which Cx43 gap junctions are down-regulated in cancer are unknown, data obtained on cell lines indicate that the frequent absence of Cx43 protein is correlated with decreased mRNA expression and the loss of GJIC (i.e., HBL-100 cells).4 Interestingly, Hs578T cells express abundant levels of Cx43, which is assembled into functional gap junctions, whereas MDA-231 cells express significant amounts of Cx43, but these cells assemble few gap junctions and remain communication-deficient.4 These results suggest that there is considerable GJIC heterogeneity in human breast carcinomas cells in vitro. It is possible that MDA-231 cells represent a subtype of human carcinomas in vivo where low levels of Cx43 are expressed but inefficiently assembled into gap junctions. No gene rearrangement was found in the various human breast cancer cell lines tested (data not shown); however, this does not exclude the occurrence of mutations that alter transcription of the gene. Both transcriptional and posttranscriptional regulation of Cx43 have been reported (Ref. 16 , reviewed in Ref. 20 ). Cx43 can be phosphorylated by protein kinase C and mitogen-activated protein kinases, whereas the phosphorylation of Cx43 by v-Src tyrosine protein kinase results in the inhibition of GJIC (16) . The ras oncoprotein is also known to disrupt GJIC, possibly through the activation of mitogen-activated protein kinase (16) . These cell signaling pathways are coupled to several growth factor receptors including erbB-2, and it is possible that coordinated regulation pathways play a role in Cx43 down-regulation.
In summary, this study demonstrates decreased expression of Cx43 gap junctions in breast cancer at various stages of progression. The lack of Cx43 gap junctions in breast cancer may serve as a diagnostic marker for breast carcinogenesis and may act as a potential therapeutic target. Earlier studies indicated that restoration of Cx43 in cells lacking Cx43 can reverse the transformed phenotype (34 , 35) , suggesting that a strategy to express functional Cx43 may be of therapeutic value. Furthermore, we and others have reported that the restoration of Cx43 expression or a chemical induction of Cx43 in tumor cells can enhance the bystander effect in gene therapy approaches using suicide gene prodrug targeting (51 , 52) . Together, these observations indicate that specific modulators of Cx43 may have therapeutic implications in cancer.
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FOOTNOTES |
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1 This work was supported by the Canadian Breast Cancer Research Initiative-National Cancer Institute of Canada Grant 009233 (to D. W. L., M. A. A-J., G. B.) and the McGill Centre for Translational Research in Cancer (to D. W. L., L. A., M. A. A-J.). 
2 To whom requests for reprints should be addressed, at Lady Davis Institute for Medical Research, Room 523, 3755 Chemin de la Côte-Ste-Catherine, Montreal, Quebec, Canada, H3T 1E2. Phone: (514) 340-8260 ext. 3438; Fax: (514) 340-7576; E-mail: mdaj{at}musica.mcgill.ca
3 The abbreviations used are: GJIC, gap junctional intercellular communication; Cx, connexin; DCIS, ductal carcinoma in situ; ILC, infiltrating lobular carcinoma; IDC, infiltrating ductal carcinoma; DMBA, dimethylbenz(a)anthracene; ER, estrogen receptor; PGR, progesterone receptor.
Received 1/19/99. Accepted 6/15/99.
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