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© The Rockefeller University Press,
0021-9525/1997//1025 $5.00
The Journal of Cell Biology, Volume 139, Number 4,
, 1997 1025-1032
Article |
Precocious Mammary Gland Development in P-Cadherin–deficient Mice
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Department of Biophysics, Faculty of Science, Kyoto University, Kitashirakawa, Sakyo-ku, Kyoto, 60601, Japan; Departments of Obstetrics and Gynecology; and || Molecular and Cellular Engineering, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
To investigate the functions of P-cadherin in vivo, we have mutated the gene encoding this cell adhesion receptor in mice. In contrast to E- and N-cadherin– deficient mice, mice homozygous for the P-cadherin mutation are viable. Although P-cadherin is expressed at high levels in the placenta, P-cadherin–null females are fertile. P-cadherin expression is localized to the myoepithelial cells surrounding the lumenal epithelial cells of the mammary gland. The role of the myoepithelium as a contractile tissue necessary for milk secretion is clear, but its function in the nonpregnant animal is unknown. The ability of the P-cadherin mutant female to nurse and maintain her litter indicates that the contractile function of the myoepithelium is not dependent on the cell adhesion molecule P-cadherin. The virgin P-cadherin–null females display precocious differentiation of the mammary gland. The alveolar-like buds in virgins resemble the glands of an early pregnant animal morphologically and biochemically (i.e., milk protein synthesis). The P-cadherin mutant mice develop hyperplasia and dysplasia of the mammary epithelium with age. In addition, abnormal lymphocyte infiltration was observed in the mammary glands of the mutant animals. These results indicate that P-cadherin–mediated adhesion and/or signals derived from cell–cell interactions are important determinants in negative growth control in the mammary gland. Furthermore, the loss of P-cadherin from the myoepithelium has uncovered a novel function for this tissue in maintaining the undifferentiated state of the underlying secretory epithelium.
CLASSICAL cadherins, such as E-, N-, and P-cadherin, play critical roles in tissue morphogenesis as evidenced by studies in Xenopus and mice (Kintner, 1992; Hermiston and Gordon, 1995). Cadherins are a family of glycoproteins involved in Ca++-dependent, homotypic cell–cell adhesion (Takeichi, 1995; Gumbiner, 1996). Classical cadherins have five extracellular domains, one transmembrane domain, and a highly conserved cytoplasmic domain. Two subclasses of cadherins, E- and P-cadherin, are detected in various epithelial tissues of mouse embryos (Nose and Takeichi, 1986). Antibody perturbation experiments have shown that E- and P-cadherin function cooperatively in the histogenesis of embryonic lung and lip skin in organ explant cultures (Hirai et al., 1989a, b). In the case of the lung primordia, addition of anti-E-cadherin antibodies resulted in collapsed lobules with little luminal space, while anti–P-cadherin antibodies had a less dramatic effect. However, a mixture of both antibodies had a synergistic effect resulting in a severely distorted epithelium that could not undergo the normal branching process. In similar experiments performed on embryonic skin, P-cadherin appears to be more important compared with E-cadherin, but again disruption of both E- and P-cadherin produced the more dramatic effect on skin morphogenesis. Taken together, these studies suggest that both E- and P-cadherin play important roles in maintaining the structural integrity of epithelial tissues.
The cadherin cytoplasmic domain interacts with a group of proteins termed catenins, which link the cadherin to the actin cytoskeleton. Interaction with both the catenins and the actin cytoskeleton is necessary for full cadherin adhesive activity (Kemler, 1993). Either β-catenin or plakoglobin, which are members of the Armadillo family of proteins (Peifer, 1995), binds directly to the cadherin. In addition to playing structural roles in cell–cell adhesion, these two catenins, along with Armadillo, appear to have signaling roles, although the exact mechanism is not fully understood. Armadillo is the product of a Drosophila segment polarity gene and is part of the wingless signaling pathway, downstream of Zeste-White 3 kinase (Peifer et al., 1994). β-catenin and plakoglobin have been implicated in formation of mesoderm and the anterior-posterior axis in the Xenopus embryo (Heasman et al., 1994; Funayama et al., 1995). Recently, β-catenin was shown to interact with the transcription factor, LEF-1, providing evidence that β-catenin can regulate gene expression (Behrens et al., 1996). 
-catenin, which shares homology with the cytoskeleton-associated protein vinculin, binds the cadherin indirectly through β-catenin or plakoglobin. Like vinculin, -catenin binds to both -actinin and actin (Knudsen et al., 1995; Rimm et al., 1995). Thus, -catenin serves to link the cadherin/catenin complex to the actin cytoskeleton.
Cell adhesion molecules, including the cadherins, are known to play important roles in mammary gland morphogenesis. The mammary gland develops postnatally under the proper hormonal stimuli during puberty and adolescence. The morphogenesis of the mammary ductal tree occurs when the end buds invade the surrounding fatty stroma until they reach the edge of the fat pad. The end buds of the mammary ducts represent the growth points for ductal morphogenesis. The end buds consist of basally located cap cells and lumenal epithelial cells (Williams and Daniel, 1983). The cap cells are loosely adhering epithelial cells that lack cytoplasmic polarity and a well organized cytoskeleton. During early pregnancy lateral buds differentiate from the ducts and during the second half of pregnancy these alveoli develop into fully differentiated secretory lobules. These morphogenetic events are accompanied by cellular differentiation leading to development of secretory epithelial cells which are capable of synthesizing and secreting milk proteins.
The mammary duct consists of two main cell types, the lumenal epithelial cells and a surrounding monolayer of myoepithelial cells with a closely apposed basement membrane. The myoepithelial cells are thought to differentiate from the cap cells extending their cell processes laterally along the duct. In the pregnant animal, the myoepithelium is present all along the duct and in the alveoli, where myoepithelial cells are basket shaped resulting in space between the cells allowing direct contact between the alveolar epithelial cells and the basal lamina. In contrast with other tissues, the expression pattern of E- and P-cadherin in the mammary gland is very distinct. In the mouse, cap cells and myoepithelial cells express P-cadherin while the lumenal epithelial cells express E-cadherin (Daniel et al., 1995). Function-blocking antibodies were used in situ to examine the role of E- and P-cadherin in maintaining the tissue integrity of the end bud (Daniel et al., 1995). Antibody to E-cadherin induced disruption of the epithelium resulting in freely floating epithelial cells in the lumen. In contrast, antibody to P-cadherin had no effect on the lumenal layer but partially disrupted the basally located cap cell layer. These data show that E- and P-cadherin are important for maintaining the integrity of the different cell layers of the mammary duct.
The cell–cell and cell–matrix interactions of myoepithelial cells may play an important role in maintaining the structural integrity of the mammary duct. Myoepithelial cells are specialized contractile cells, whose ultrastructure is reminiscent of smooth muscle cells (Deugnier et al., 1995). They express smooth muscle contractile and cytoskeletal proteins such as -smooth muscle actin (Radnor, 1972). However, they are true epithelial cells since cytokeratin is the major component of the intermediate filament system, they form desmosomes, hemidesmosomes, and adherens junctions, and are permanently separated from the connective tissue by the underlying basement membrane (Franke et al., 1980; Sonnenberg et al., 1986; Rasbridge et al., 1993).
Recent experiments suggest that myoepithelial cells may have an important role in branching morphogenesis in the mammary gland (Niranjan et al., 1995). Hepatocyte growth factor/scatter factor (HGF/SF)1 is produced by the fibroblasts in the breast. The lumenal epithelium and myoepithelium respond differently to HGF/SF; which acts as a mitogen for the lumenal cells while it behaves like a morphogenic factor for the myoepithelial cells. Human myoepithelial cells exposed to HGF/SF form extended branching tubules while lumenal epithelial cells did not show any morphological changes (Niranjan et al., 1995). Furthermore, overexpression of HGF/SF in the mammary gland of transgenic mice leads to precocious alveolar differentiation (Takayama et al., 1997). These data suggest that myoepithelial cells may play an important role in branching morphogenesis in the mammary gland.
To understand the role of the P-cadherin adhesion receptor in mouse development, we mutated the P-cadherin gene in embryonic stem (ES) cells and introduced the mutation into the mouse germ line (Capecchi, 1989). In contrast to E- and N-cadherin knockout mice, the P-cadherin–deficient mice are viable and fertile. However, the P-cadherin–null females exhibit precocious differentiation of the mammary gland and display mammary hyperplasia later in life. The P-cadherin–deficient mice provide us with a valuable model to determine the role of P-cadherin in cell proliferation and differentiation in the mammary gland.
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Materials and Methods |
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Western Immunoblotting
Decidual tissue from wild-type, heterozygous, and homozygous conceptuses was isolated on day 8 of gestation. The protein lysates were subjected to SDS-PAGE (Laemmli, 1970), and the resolved proteins were transferred electrophoretically to nitrocellulose. The blot was reacted with antibodies to P-cadherin (PCD-1; Nose and Takeichi, 1986) and protein bands were visualized using the ECL (Amersham Corp., Arlington Heights, IL) detection system.
Morphological and Histological Analysis
The thoracic no. 3 and/or inguinal no. 4 mammary glands were examined. Whole mount staining of the glands was performed as previously described (Williams and Daniel, 1983). The mammary glands were fixed overnight in Tellyesniczky's fixative (5% formalin, 5% acetic acid, 70% EtOH). The fixed glands were defatted in acetone, stained with: hematoxylin (0.65g FeCl3, 67.5 ml H2O, 8.7 ml stock hematoxylin [10% in 95% ethanol], and 1,000 ml 95% ethanol, adjust pH 1.25 with concentrated HCl), and then rinsed in tap water, dehydrated in increasing concentrations of ethanol to xylene, and photographed with a dissecting microscope.
For histology, mammary glands were fixed in 10% formalin, processed for paraffin sectioning, and stained with hematoxylin and eosin.
Immunohistochemistry
Immunostaining for P- and E-cadherin, -smooth muscle actin, and caseins was performed on frozen sections of mammary tissue as described previously (Daniel et al., 1995). Tissue was embedded in Tissue-Tek OCT compound (Miles Diagnostic Division, Elkhart, IN) and frozen in an isopentane/dry ice bath. 8-µm sections were cut with a Zeiss cryotome, placed on Superfrost Plus slides (Fisher Scientific, Pittsburgh, PA), postfixed in 1:1 acetone/methanol at –20°C for 10 min, air dried, and stored at –20°C. Antibodies were diluted in 5% skim milk/PBS except for casein antibody (1% goat serum/PBS) as follows: rat monoclonal PCD-1 (1:200), rat monoclonal ECCD-2 (1:500; Shirayoshi et al., 1986), mouse monoclonal -smooth muscle actin (clone 1A4, 1:400; Sigma Chemical Co., St. Louis, MO), and rabbit polyclonal casein (1:1,000; a gift from Charles Daniel, University of California, Santa Cruz). The samples were incubated overnight with primary antibodies except casein antibody (1 h), washed with PBS, incubated with species specific biotinylated secondary antibodies (Amersham), washed with PBS, and processed with Vectastain ABC reagents (Vector Labs, Burlingame, CA), regular or elite, and washed with PBS. The casein antibody washes contained 1% goat serum. The peroxidase substrate was applied, sections were lightly counterstained with hematoxylin, dehydrated, and coverslipped. The samples were photographed with a Nikon Optiphot microscope.
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P-Cadherin Mutant Mice Are Viable and Fertile
To examine whether animals homozygous for the P-cadherin mutation were viable, heterozygous animals were intercrossed and genotypes of the progeny were determined by Southern blot or by PCR analysis. Mice homozygous for the P-cadherin mutation were detected among the intercross progeny (Fig. 1 C). The genotypes of the progeny showed a good fit to Mendelian distribution (107 +/+: 211 –/+:114 –/–). Homozygous P-cadherin–deficient mice did not show any overt developmental abnormalities and were indistinguishable from their heterozygous or wild-type littermates on the basis of size, activity, or fertility. To determine whether wild-type P-cadherin protein was present in homozygous mice, we examined the uterine decidua of pregnant mice since P-cadherin protein is very abundant in this maternal tissue. The decidual tissue without the embryo and extraembryonic membranes was isolated from day 8 conceptuses of wild-type, heterozygous, and homozygous mice. Western blot analysis of decidual lysates was performed using monoclonal antibody, PCD-1, which recognizes the amino terminus of the protein (Nose et al., 1990). No full-length or truncated P-cadherin protein was detected in the mutant, while a reduced amount of P-cadherin protein was present in the heterozygote (Fig. 1 D). In addition, a pan-cadherin polyclonal antibody (Takeichi et al., 1990) which recognizes the conserved cytoplasmic domain of classical cadherins did not detect P-cadherin in the mutant decidual tissue (data not shown).
To determine if loss of P-cadherin affected litter size, hybrid 129Sv/C57BL mutant males and females were mated. The P-cadherin–null females had litter sizes (average 8.8, 114 pups/13 litters) comparable to their wild-type littermates. The ability of the P-cadherin mutant females to nurse and maintain a normal size litter indicates that the contractile function of the myoepithelium is not dependent on the cell adhesion molecule P-cadherin.
Loss of P-Cadherin from Myoepithelial Cells Leads to Alveolar Differentiation in Virgin Females
To examine cadherin expression in the mutant mammary duct, immunohistochemistry was performed on sections of mammary tissue. P-cadherin was localized to the myoepithelial cells surrounding the lumenal epithelial cells in the wild-type, but absent from the mutant duct (Fig. 2, A and D). The presence of myoepithelium in the mutant duct was confirmed by smooth muscle actin staining (Fig. 2, B and E), a marker for myoepithelial cells (Radnor, 1972). E-cadherin expression was similar in wild-type and mutant ducts (Fig. 2, C and F), thus demonstrating that E-cadherin expression was not affected by mutating the closely linked P-cadherin gene (Hatta et al., 1991).
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Ductal morphogenesis in the mammary gland occurs during puberty when the end buds of the ducts invade the surrounding fatty stroma until they reach the edge of the fat pad. The cells surrounding the end buds, called cap cells, are thought to play an important role in ductal growth and branching morphogenesis. P-cadherin is expressed by the cap cells and function-blocking antibodies can disrupt the cellular integrity of the end bud (Daniel et al., 1995). However, ductal morphogenesis appears normal in the mutant mice, indicating that P-cadherin is not required by the cap cells for invasion of the surrounding fat pad. There are presumably other cell adhesion molecules expressed by the cap cells which can functionally substitute for P-cadherin in the mutant mammary glands. Normally, the mammary gland does not differentiate fully until the onset of pregnancy when lateral buds develop as side branches of the mammary tree. The alveoli develop further during the second half of pregnancy into fully differentiated secretory lobules capable of synthesizing and secreting milk proteins. The P-cadherin–deficient females display precocious differentiation of the mammary epithelium similar to an early pregnant animal. Furthermore, the mutant virgin glands synthesize milk protein (i.e., casein) indicative of a differentiated mammary epithelium.
How might loss of P-cadherin cause the mammary gland phenotype? The possibility that P-cadherin is normally downregulated during early pregnancy leading to alveolar differentiation is intriguing. However, Northern blot analysis did not detect any change in P-cadherin expression between virgin and early, mid, or late pregnant mammary glands (D'Cruz, C.M., G.L. Radice, and L.A. Chodosh, unpublished data). The fact that the P-cadherin–null females lactate and nurse their pups implies that the myoepithelium can still perform its function as a contractile tissue, however, subtle defects in cell adhesion may be possible. While there is considerable evidence for inductive signals from the stroma and extracellular matrix (ECM) affecting the differentiation of the lumenal epithelium (Roskelley et al., 1995), there is very little information about the role of the myoepithelium in this process, even though it separates the stroma and basal lamina from the lumenal epithelial cells. The myoepithelium is situated in a unique position to regulate signals from the surrounding ECM and stroma to the underlying epithelium, the indirect regulation model (Fig. 6 A). The myoepithelium consists of a monolayer of cells that probably does not represent a physical barrier per se, but it may act as a filter to transmit specific signals to the underlying epithelium. P-cadherin–mediated adhesion may be important for the assembly of other junctional complexes. A cell adhesion defect may perturb intercellular communication (i.e., gap junction assembly) in the myoepithelium leading to altered growth signals. The loss of P-cadherin may affect the function of other cell adhesion molecules, for example, integrin- mediated ECM interactions may be compromised leading to changes in cell morphology of the myoepithelial cells.
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The cadherin/catenin adhesion complex and the Wnt signaling pathway share a common component, β-catenin. Data from transgenic and mutant mice suggest that the P-cadherin–null phenotype may be due to activation of the Wnt signaling pathway. Transgenic mice that overexpress Wnt-1 in the mammary gland develop extensive alveolar hyperplasia and adenocarcinomas (Tsukamoto et al., 1988). In addition, mutation of another member of the Wnt signaling pathway, Adenomatous polyposis coli (APC), predisposes mice to focal alveolar hyperplasia and carcinomas (Moser et al., 1993). APC is a negative regulator of the intracellular β-catenin pool, hence when APC is active the cytoplasmic pool of β-catenin is very low. When the Wnt pathway is activated, APC is turned off, and β-catenin accumulates in the cytoplasm. β-catenin can then interact with the DNA binding proteins of the T cell factor-lymphoid enhancer factor (Tcf-Lef) family to activate transcription of target genes (Behrens et al., 1996). The loss of P-cadherin may increase the available cytoplasmic β-catenin thus activating the Wnt signaling pathway resulting in transcription of growth factor genes whose gene products induce differentiation of the neighboring epithelial cells, the direct regulation model (Fig. 6 B). This scenario assumes that APC cannot efficiently inactivate the excess β-catenin present in the P-cadherin–deficient mammary gland.
Ectopic or overexpression of several proteins including Wnt1 (Tsukamoto et al., 1988), growth hormone (Bchini et al., 1991), HGF/SF (Takayama et al., 1997), and stromelysin1 (Sympson et al., 1994) lead to extensive alveolar hyperplasia and mammary tumors in transgenic mice. The extent of precocious alveolar differentiation observed in the P-cadherin–deficient mice appears less dramatic in comparison to these other transgenic strains. No palpable tumors were observed in the mutant animals, although, focal hyperplastic and dysplastic lesions were observed in the mutant mammary glands upon necropsy. Hyperplasia was also observed in the salivary gland where P-cadherin is normally expressed in the myoepithelial cells (Ferreira-Cornwell, M.C. and G.L. Radice, unpublished data). The finding that disruption of P-cadherin function alone is not sufficient to induce mammary tumors, suggests that additional genetic lesion(s) are necessary to progress beyond the hyperplastic phenotype.
P-cadherin is also expressed in myoepithelial cells of the human mammary gland suggesting that loss of function of this cell adhesion molecule may promote cell growth and differentiation in the human breast. While most attention has focused on the role of E-cadherin in breast cancer, our data suggest that P-cadherin may also be involved. Loss of heterozygosity (LOH) of 16q22.1 has been implicated in many types of cancer including breast (Birchmeier and Behrens, 1994). E- and P-cadherin are tandemly arranged at this locus separated by only 32 kb of genomic DNA (Bussemakers et al., 1994). While cadherin expression has been examined extensively in the tumor tissue itself, perturbation of cadherin function in the surrounding myoepithelium has not been addressed. Germline mutations in the human P-cadherin gene may predispose women to breast cancer since hyperplastic growth is an early step in tumor development.
Recently, a novel cadherin, H-cadherin, was found to be expressed in human mammary epithelial cells (Lee, 1996). H-cadherin lacks a cytoplasmic domain and is most similar to T-cadherin (Ranscht and Dours-Zimmermann, 1991). Its expression was found to be significantly reduced in human breast carcinoma cell lines and primary breast tumors (Lee, 1996). Furthermore, transfection of H-cadherin into the breast cancer cell lines led to a decreased cell growth rate and loss of anchorage-independent growth in soft agar. These data suggest that two distinct cadherins, H- and P-cadherin, are involved in negative growth control in the mammary gland.
Several loss of function mutations in the mouse result in disruption of mammary gland development and function. Mutations in cyclin D1 (Sicinski et al., 1995), activin/inhibin βB (Vassalli et al., 1994), progesterone (Lydon et al., 1995), and prolactin receptors (Ormandy et al., 1997), and Stat5a (Liu et al., 1997) all result in inhibition of lobuloalveolar outgrowth in the mammary gland. All these gene products are positive effectors in a signaling pathway(s) leading to alveolar cell proliferation and differentiation. In contrast, P-cadherin appears to act as a negative regulator of cell growth and differentiation in the mammary gland. Its absence leads to precocious alveolar differentiation in virgin animals.
In conclusion, gene targeting of the cell adhesion receptor, P-cadherin, has uncovered a novel function for this molecule in negative growth control of the mammary gland. The mechanism by which P-cadherin acts to control cell growth remains to be determined. No obvious cell adhesion defect has been observed in the myoepithelium of the mutant animals so far, suggesting the mammary gland phenotype may result from perturbation of cellular signals involved in negative growth control.
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Acknowledgments |
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Submitted: 17 July 1997
Revised: 28 August 1997
1. Abbreviations used in this paper: APC, adenomatous polyposis coli; ECM, extracellular matrix; ES, embryonic stem; HGF/SF, hepatocyte growth factor/scatter factor; HSV, Herpes simplex virus; PCD-1, P-cadherin antibody.
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