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Breast Cancer Metastatic Potential Correlates with a Breakdown in Homospecific and Heterospecific Gap Junctional Intercellular Communication¹

Departments of Orthopaedics and Rehabilitation [M. M. S., Z. L., Z. Z., H. J. D.] and Cellular and Molecular Physiology [H. J. D.] and Jake Gittlen Cancer Research Institute [C. R. W., D. R. W.], The Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, and Department of Urology, University of Virginia, Charlottesville, Virginia 22908 [M. J. S.]

	ABSTRACT

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Breast cancer progresses toward increasingly malignant behavior in tumorigenic and metastatic stages. In the series of events in the metastatic stage, tumor cells leave the primary tumor in breast and travel to distant sites where they establish secondary tumors, or metastases. In this report, we demonstrate that cell-cell communication via gap junctions is restored in the metastatic human breast carcinoma cell line MDA-MB-435 when it is transfected with breast metastasis suppressor 1 (BRMS1) cDNA. Furthermore, the expression profile of connexins (Cxs), the protein subunits of gap junctions, changes. Specifically, the expression of BRMS1 in MDA-MB-435 cells increases Cx43 expression and reduces Cx32 expression, resulting in a gap junction phenotype more similar to normal breast tissue. Taken together, these results suggest that gap junctional communication and the Cx expression profile may contribute to the metastatic potential of these breast cancer cells.

	Introduction

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GJIC³ has been linked previously to tumorigenesis (1 , 2) and progression toward metastasis (3, 4, 5) . Gap junctions are membrane-spanning channels composed of protein subunits called Cxs that facilitate GJIC by allowing small (M_r <1000) signaling molecules to pass from cell to cell. GJIC may be homospecific, coupling cells of the same type, or heterospecific, coupling cells of unlike type (6) . In tumorigenesis, a breakdown in homospecific and heterospecific coupling has been demonstrated to precede neoplasia and has been hypothesized as necessary to maintain malignant phenotype transformation (2) . We propose that this breakdown in communication also contributes to metastatic potential in human breast carcinoma cells. To explore this possibility, we examined the hypothesis that metastatic potential correlates with gap junction expression and function quantified in vitro. The breast cancer model we used compared MDA-MB-435 cells (MDA 435) and these cells expressing the recently described metastasis suppressor gene, BRMS1 (435-BRMS1; Ref. 7 ). MDA 435 and 435-BRMS1 cells provide a powerful model to study metastasis because they have genetically identical backgrounds, thus reducing biological noise otherwise present when comparing genetically unrelated heterologous tumor cell lines. In this study, we demonstrate that introduction of BRMS1 cDNA reestablishes both homospecific and heterospecific GJIC function and alters the pattern of gap junction protein (Cx) expression.

	Materials and Methods

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Cell Culture.
Four cell lines were used in this study. The metastatic cell line MDA 435 was derived from pleural effusion from a female patient with an infiltrating ductal carcinoma (8) . 435-BRMS1 are MDA 435 cells transfected with BRMS1 cDNA driven by the CMV promoter (7) . 435pVC are MDA 435 cells expressing plasmid vector (pcDNA3; Invitrogen, Carlsbad, CA) only and served as a control for transfections (7) . HS578Bst is an immortalized nontumorigenic, nonmetastatic breast epithelial cell line (9) purchased from American Type Culture Collection. They were used to represent normal breast epithelial cells. The MDA 435 cell line was maintained in DMEM/F12 cell culture medium (Life Technologies, Inc., Rockville, MD) containing 5% fetal bovine serum. 435pVC and 435-BRMS1 lines were maintained in this same medium supplemented with geneticin (500 µg/ml). HS578Bst cells were maintained in DMEM (Life Technologies) supplemented with 10% fetal bovine serum and epidermal growth factor (30 ng/ml). Cells were passaged using a 2 mM EDTA solution in calcium- and magnesium-free Dulbecco’s PBS.

Assessment of GJIC.
To corroborate GJIC assays, two complimentary techniques were used, as described previously (10) . Homospecific and heterospecific GJIC were functionally assessed using double labeling fluorescent dye transfer assays (11) and direct cell injections (10) . Homospecific coupling was assessed for the three tumorigenic cell lines: MDA 435, 435pVC, and 435-BRMS1. Heterospecific coupling was assessed among the three tumorigenic cell lines in all possible combinations, as well as with the nontumorigenic, nonmetastatic human breast line, HS578Bst.

For double labeling assays, "acceptor" cells were plated at a density of 4 x 10⁴ cells/cm² to round (25-mm) glass coverslips placed previously in round (35-mm) polystyrene Petri dishes. Cells were allowed to reach 90% confluence at 37°C in a humidified CO₂ incubator over a period of 24–48 h. Simultaneously, "donor" cells were plated at a density of 4 x 10⁴ cells/cm² in 35-mm tissue culture dishes and maintained at 37°C over the same time period. GJIC was quantified as described previously (12) . Briefly, donor cells were labeled with a fluorescent dye mixture containing calcein AM (Molecular Probes, Eugene, Oregon) and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (Molecular Probes), detached, centrifuged, resuspended in fresh growth medium, and counted using a hemacytometer. Double-labeled donor cells were then dropped onto confluent monolayers of unlabeled acceptor cells at a ratio of approximately 1:500 (labeled:unlabeled) cells and incubated for 90 min at 37°C. After incubation, the coverslips were removed from the dishes, washed twice with room temperature PBS, and inverted onto clean, glass microscope slides and evaluated using a Nikon epifluorescence microscope (Nikon EFD-3; Optical Apparatus Co., Ardmore, PA). Calcein, because of its small molecular size (M_r 994,870), diffuses to neighboring cells via GJIC. The fluorescent dye, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate, intercalates within cell membranes and does not transfer to neighboring cells via GJIC but is used to visualize the donor cell.

For direct cell injections, cells were plated at a density of 3.5 x 10⁴ cells/cm² on round (25-mm) glass coverslips in tissue culture dishes and examined at 90% confluence. Cells were washed twice with room temperature PBS and sandwiched in a metal and nylon well affixed to the fluorescent microscope and submerged in room temperature PBS throughout the duration of the experiment. Individual cells were impaled with glass micropipettes that had been backfilled with a fluorescent dye mixture of Lucifer yellow (Molecular Probes) dissolved in lithium chloride. Cells were impaled 3 min, the pipette was removed, and dye transfer was monitored for an additional 2 min. In preliminary experiments, it was found that 435-BRMS1 cells did not adhere firmly to glass substrates. Therefore, in an attempt to optimize cell attachment, we plated 435-BRMS1 cells onto coverslips coated with collagen type I (10 µg/cm²) and type II (.5 mg/ml), fibronectin (10 µg/cm²), Matrigel (1 mg/ml), Cell-tak (1 mg/ml), poly-D-lysine (5 µg/cm²), and poly-L-lysine (5 µg/cm²) purchased from Becton Dickinson (Bedford, MA). We found that poly-D-lysine coating provided optimal conditions for our experiments; therefore, all experiments reported are from cells plated on poly-D-lysine.

Northern Blot Analysis of Cx mRNA Expression.
Steady-state mRNA levels of the gap junction proteins Cx26, Cx32, Cx43, Cx45, and Cx46 were quantified by Northern blot analysis for all four cell lines examined. Cells were plated at a density of 2 x 10⁴ cells/cm² in 100-mm tissue culture dishes and cultured to confluence, and total RNA was isolated as described (11) . Briefly, total RNA (20 µg), as determined by absorption at 260 nm, was subjected to electrophoresis on a 1% agarose formaldehyde gel. The gels were then capillary blotted with 100 mM sodium phosphate onto membranes (Gene Screen Hybridization Transfer Membrane; DuPont NEN) and prehybridized for 15 min at 55°C in 1% BSA, 350 mM sodium phosphate, 7% SDS, and 30% (v/v) deionized formamide and followed by hybridization overnight in the same solution with [-³²P]dCTP-labeled probes for the 1.3-kb coding region of Cx43 cDNA, the entire 1.2-kb coding region of Cx45 cDNA, an EcoRI fragment of rat Cx46 cDNA, a 1.1-kb HincII-Bst fragment of Cx26 cDNA, a full-length 1.5-kb cDNA for Cx32 cDNA, or a 1.4-kb PstI fragment of rat glyceraldehyde 3-phosphate dehydrogenase cDNA. The blots were washed once in 150 mM sodium phosphate and 0.1% SDS at room temperature, followed by two washings at 55°C.

	Results

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Quantification of Dye Coupling.
To examine homospecific GJIC, >450 individual 435 and 435pVC cells were analyzed by double labeling in addition to 15 cells by direct injection. No evidence of homospecific GJIC was observed using either technique. Fig. 1a shows a plate of 435 cells in monolayer (black) with the double-labeled cells shown in yellow in the dual exposure photograph (x400). As evidenced by the lack of dye transfer, MDA 435 cells were not functionally coupled and therefore not able to communicate with themselves via gap junctions. This was corroborated with the direct cell injection technique, in which Lucifer yellow remained in the injected cell and did not spread (Fig. 1c) . More than 300 individual 435-BRMS1 cells were analyzed by double labeling, and 8 cells were analyzed by direct injection. Coupling was observed using double labeling (Fig. 1b , note donor cells appear yellow, whereas neighboring acceptor cells appear green) and in seven of eight injected cells (Fig. 1d , note that both the injected cell and neighboring cells appear yellow). From cell counting, it was estimated that a single injected cell transferred dye to >500 neighboring cells, indicating that coupling was extensive.

View larger version (121K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. Homospecific GJIC in breast cancer cell lines. Parent MDA 435 (a) or 435-BRMS1 (b) were grown in monolayer and subjected to double labeling assays. Calcein-loaded MDA 435 donor cells were placed in contact with monolayer MDA 435 acceptor cells (a), and calcein-loaded 435-BRMS1 donor cells were placed in contact with monolayer 435-BRMS1 acceptor cells (b). Neither MDA 435 nor 435pVC displayed homospecific GJIC, whereas 435-BRMS1 did. Individual MDA 435 (c) or 435-BRMS1 (d) cells were injected with Lucifer yellow. Dye remained within MDA 435 cells but transferred from the injected 435-BRMS1 to neighboring 435-BRMS1, indicating homospecific coupling within an elapsed time of 5 min. x400. Arrows, injected cells.

Expression of Cx mRNA.
We did not detect mRNA for Cx26, Cx45, or Cx46 (data not shown) in any of the cell lines examined. However, Cx43 mRNA was highly expressed in HS578Bst cells and 435-BRMS1 cells, albeit less abundantly in the latter. On the other hand, Cx43 mRNA was not detected in MDA 435 or 435pVC cells (Fig. 2) . Interestingly, although Cx32 mRNA was highly expressed in 435 and 435pVC, it was not detected in HS578Bst and 435-BRMS1 cells (Fig. 3) . These findings were consistent with three separate experiments.

View larger version (37K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. Cx43 mRNA expression in human breast epithelial cells and breast cancer cell lines. Cells were cultured to confluence and steady-state Cx43 (upper panel) and GAPDH (lower panel) mRNA levels assessed by Northern blot analysis. Neither metastatic MDA 435 or 435pVC (pcDNA3-transfected) cells expressed Cx43. Human breast epithelial cells (HS578Bst) expressed Cx43, and Cx43 was moderately expressed in the metastasis-suppressed 435-BRMS1 cells. This result is typical of three similar experiments.

View larger version (36K): [in this window] [in a new window] [Download PPT slide]   Fig. 3. Cx32 mRNA expression in human breast epithelial cells and breast cancer cell lines. Cells were cultured to confluence, and steady-state Cx32 (upper panel) and GAPDH (lower panel) mRNA levels were assessed by Northern blot analysis. Neither human breast epithelial cells (HS578Bst) nor metastasis-suppressed 435-BRMS1 cells expressed Cx32. Both MDA 435 and 435pVC expressed Cx32. This result is typical of three similar experiments.

	Discussion

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Cx43 is the predominant gap junction protein in normal breast epithelial tissue (13) , but the expression of Cx26 in normal breast epithelial tissue is less clear. Some groups have failed to detect Cx26 in normal mammary tissue, whereas other groups have (14 , 15) . The expression of other Cxs, including Cx32, has not been reported in human breast tissue, but in mice Cx26 and Cx32 have been reported in breast tissue during pregnancy and lactation, respectively (16) .

In the HS578Bst breast epithelium-derived cells, Cx43, but not Cx26 or Cx32, was expressed. On the other hand, metastatic MDA 435 cells expressed neither Cx26 nor Cx43, consistent with the loss of Cx43 expression reported in neoplastic breast tissue (15) , but did express Cx32. Restoring BRMS1 expression results in reestablishment of GJIC but only partly restored Cx43 expression. This suggests the possibility of novel Cxs in 435-BRMS1 cells or, more likely, that a relatively low level of Cx43 expression is sufficient for establishing detectable GJIC. A more striking finding was that although metastatic MDA 435 cells expressed Cx32, metastasis-suppressed 435-BRMS1 cells did not. To our knowledge, Cx32 has not been thoroughly examined in tumorigenic and metastatic breast cancer cells. To date, the only study examining Cx32 in neoplastic tissue failed to detect it in breast carcinoma (15) . Our data suggest that re-expression of the metastasis-suppressor gene BRMS1 returns the Cx expression profile from that of a metastatic cell (Cx32 but not Cx43) to that more similar to a normal breast epithelial cell (Cx43 but not Cx32). Furthermore, although BRMS1 expression restores, at least in part, Cx43 mRNA expression, it may inhibit Cx32 mRNA expression. At minimum, these data imply that the composition of gap junctions contributes to metastatic propensity. It is also possible, although more extensive studies are required, that Cx32 expression contributes to breast cancer cell metastatic potential.

The mechanism by which altered Cx expression and GJIC might contribute to metastasis is unclear. One possibility is that deficient heterospecific GJIC between cancer cells and normal breast epithelial cells contributes to detachment of the malignant cells from the primary tumor. This concept is supported by studies showing a relationship between E-cadherin, a cell-cell adhesion molecule that is down-regulated in many tumors (17) , and gap junction expression and function (18) . However, none of the MDA 435 variants express E-cadherin (7) , suggesting that E-cadherin may contribute to tumorigenesis but not metastatic potential. This does not preclude the possibility that altered Cx expression and GJIC may regulate other cell adhesion molecules that could contribute to the detachment of malignant cells from the primary tumor.

Another mechanism by which altered Cx expression and GJIC might contribute to metastatic potential is by facilitating arrest on, or colonization of, the secondary tumor environment. For instance, GJIC has been demonstrated between metastatic tumor cells and vascular endothelium (19) and is directly related to metastatic potential (20) . Recently, Ito et al. (3) demonstrated that B16-BL6 melanoma cells, which are metastatic after s.c. injection, expressed Cx26 and displayed GJIC with endothelial cells. However, B16-F10 melanoma cells, which did not metastasize after s.c. injection in their hands, did not express Cx26, nor did they establish GJIC with endothelial cells. Transfection with wild-type Cx26 made F10 cells as competent to communicate with endothelial cells as B16-BL6 cells. Conversely, transfection with a dominant-negative form of Cx26 rendered B16-BL6 cells deficient in GJIC and less metastatic. Taken together, these results suggest that heterospecific GJIC between tumor cells and endothelial cells, or other cells in the secondary tumor environment, may contribute to the metastatic potential of malignant cells. Future studies will address these possibilities.

In summary, the experiments presented here demonstrate two things: (a) they show that restoration of BRMS1 expression in MDA 435 cells results in concomitant reduction in metastatic efficiency and restoration of GJIC; and (b) BRMS1 expression alters Cx expression in the tumor cells. Together these findings imply that BRMS1 is acting by a novel mechanism to inhibit metastasis, and that GJIC mediated by specific Cxs may be a major determinant of metastatic potential in human breast cancer.

	ACKNOWLEDGMENTS

 
We acknowledge Dr. Clare Yellowley for technical assistance with the direct cell injections.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants AG13087 and CA87728 from the NIH, Grant BC995879 from the United States Army, and a grant from the National Foundation for Cancer Research.

² To whom requests for reprints should be addressed, at Musculoskeletal Research Laboratory, Department of Orthopaedics and Rehabilitation, The Pennsylvania State University College of Medicine, P. O. Box 850, 500 University Drive, Hershey, PA 17033. Phone: (717) 531-4818; Fax: (717) 531-7583.

³ The abbreviations used are: GJIC, gap junctional intercellular communication; Cx, connexin; BRMS1, breast metastasis suppressor 1.

Received 11/ 2/00. Accepted 1/11/01.

	REFERENCES

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