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Human Cancer Biology |
in Breast Cancer
Authors' Affiliations: 1 Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California at Los Angeles School of Medicine and 2 Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California
Requests for reprints: Sigal Gery, Cedars-Sinai Medical Center, Davis Building 5066, 8700 Beverly Boulevard, Los Angeles, CA 90048. Phone: 310-423-4609; Fax: 310-423-0225; E-mail: gerys{at}cshs.org.
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Abstract |
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is involved in breast cancer.
Experimental Design: We quantified C/EBP mRNA expression levels in 24 primary breast tumors, 16 normal breast samples, and 8 breast cancer cell lines using quantitative real-time reverse transcription-PCR assay. C/EBP protein levels were further determined by immunohistochemical analysis. To examine the consequence of C/EPB expression in breast cancer, we stably transfected an inducible C/EPB expression vector into three breast cancer cell lines.
Results: Low expression of C/EBP mRNA was found in 83% of primary breast cancer samples. Immunohistochemical study further showed either a markedly reduced or undetectable expression of C/EBP protein in 30% of breast cancer specimens. The other 70% of breast cancers had C/EBP expression in both the cytoplasm and nucleus; in control, C/EBP was localized to the nucleus in the normal ductal cells. C/EBP expression was associated with estrogen- and progesterone receptor–negative status. Induction of C/EBP expression in these cell lines resulted in growth inhibition accompanied by G0-G1 cell cycle arrest and reduced anchorage-independent cell growth. C/EBP expression was associated with down-regulation of c-myc and up-regulation of p21, PPAR
, and the breast epithelial differentiation marker, maspin.
Conclusions: These results suggest that reduced expression of C/EBP may play a role in the development and/or progression of breast cancer.
Key Words: C/EBP • antiproliferative • breast cancer
The C/EBP family is composed of six members that share a highly conserved basic region and a leucine zipper domain (bZIP). The levels of three C/EBPs (C/EBP, C/EBPß, and C/EBP
) change dramatically throughout mammary gland development (4, 5). Studies in knockout models shown that C/EBPß is vital for development of the murine mammary gland (6, 7). C/EBP, on the other hand, is not essential for mammary gland development, although C/EBP mRNA is expressed throughout this process. Likewise, mammary gland development is normal in C/EBP knockout mice. Nonetheless, results from a recent study indicated that C/EBP functions in the maintenance of mammary epithelial cell growth (8). In addition, cell culture studies determined that C/EBP plays a predominant role in growth arrest of mammary epithelial cells (9).
C/EBP, the founding member of the C/EBP family, plays a critical role in the regulation of mitotic growth arrest and differentiation in numerous cell types, including preadipocytes, myeloid cells, hepatocytes, keratinocytes, and pneumocytes (10–16). Consistent with this, C/EBP-null mice display cell proliferative defects in the liver and lung and die at birth because of energy imbalance. Furthermore, mutations in the C/EBP gene were found in a subclass of human myeloid leukemias (17, 18), implicating C/EBP as a tumor suppressor gene. Down-regulation and antiproliferative effects of C/EBP were also shown in lung cancer (19). Different models involving both transcriptional and nontranscriptional mechanisms have been proposed to explain how C/EBP causes cell cycle arrest. Initially, C/EBP was shown to regulate p21 expression and interact with the retinoblastoma (Rb) family of proteins (20–22). Later studies indicated that C/EBP can blunt growth, independent of its DNA-binding activity, by forming a complex with cdk2 and cdk4, thereby blocking cyclin-cdk interactions (23). In addition, C/EBP represses E2F target genes, such as c-myc, by directly associating with E2F; this repression is necessary for growth arrest as well as adipocyte and granulocyte differentiation (24–26). A recent study suggested that the interaction between C/EBP and the SWI/SNF chromatin-remodeling complex is critical for C/EBP–induced growth arrest (27).
Whereas studies showed that C/EBPs are implicated in the regulation of proliferation and differentiation of mammary gland, the expressions of C/EBPs in human mammary carcinomas, particularly at the mRNA level, have not been characterized in detail. In the present study, using quantitative real-time reverse transcription-PCR (RT-PCR), we found down-regulation of C/EBP mRNA expression in primary mammary carcinomas. Reduced expression of C/EBP protein was further found in primary breast cancer samples. Reestablishment of C/EBP expression in a breast cancer cell line led to inhibition of growth. These data show that C/EBP inhibits proliferation of mammary epithelial cells and should be considered a potential tumor suppressor gene in breast cancer.
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Materials and Methods |
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Real-time reverse transcription-PCR. Total RNA was extracted from cell lines and breast specimens by using TRIzol reagent (Invitrogen, Carlsbad, CA) according to the standard protocol. Quality of the RNA samples was determined by electrophoresis through agarose gels and staining with ethidium bromide. Total RNA (2 µg) was processed to cDNA by reverse transcription with Superscript II (Invitrogen) according to the manufacturer's protocol. Primers were synthesized by Invitrogen. Probes were purchased from Applied Biosystems (Foster City, CA) and were labeled with the reporter dye FAM in the 5' end and the quencher dye TAMRA in the 3' end. The sequences of the primers and probes are shown in Table 1.
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and 18S (for endogenous reference), amplification reactions were done with the Universal Taqman PCR mastermix (Applied Biosystems) in triplicates in an iCycler iQ system (Bio-Rad, Hercules, CA). The thermal cycling conditions were as follows: 2 minutes at 50°C, 10 minutes at 95°C, followed by 45 cycles of 95°C for 15 seconds, and 60°C for 1 minute. To determine the relative expression level of the C/EPB and the endogenous reference in each sample, additional reactions with four serial 5-fold dilutions of MCF-7 cDNA were done to generate a standard curve, which related the threshold cycle to the log input amount of template. The relative C/EPB expression level was also normalized to a mean value (value = 1) from 16 normal breast tissue samples. The expression values of the 16 normal breast tissues were between 0.38 and 3.61. Accordingly, the cutoff point for C/EPB underexpression was set at a value of 
0.38. Final results were expressed as N-fold difference in C/EBP gene expression relative to the 18S and the calibrator.
Expression levels of PPAR and maspin mRNA were measured with HotMaster Taq DNA Polymerase (Eppendorf, Hamburg, Germany) and SYBRGreen I (Molecular Probes). PCR conditions were as follows: 2 minutes at 94°C followed by 45 cycles of 94°C for 20 seconds, 60°C for 10 seconds, 65°C for 25 seconds, and fluorescence determination at the melting temperature of the product for 20 seconds. Specificity of PCR products was checked on agarose gel. Reactions were done in triplicates in an iCycler iQ system (Bio-Rad). For each sample, the amount of the target gene and 18S was determined from a standard curve.
Immunohistochemical analysis. The intensity of the immunostaining was graded into two categories: negative and positive. A case was categorized as showing negative staining when no staining was seen in the nuclei of the cancer cells. If some staining was observed, it was classified as positive. Varying intensity of positive staining was noted. A case was categorized as 1+ if the intensity of staining was weak and 2+ if the intensity of staining was strong. Fisher's exact test was used to study the association of the expression levels of C/EBP with the different features of the breast cancers. In 26 of these cases, adjacent normal breast tissue was present on the sections, whereas associated ductal carcinoma in situ was observed in 14 of the cases.
Cell culture and transfections. The breast cancer cell lines MCF-7, T47D, BT474, ZR75-1, MDA-MB-231, MDA-MB-468, SKBR3, and BT20 were obtained from the American Type Culture Collection (Manassas, VA) and grown in the recommended medium and conditions. The zinc-inducible C/EBP expression vector (pMT) was previously described (28). To generate stable cell lines, MDA-MB-231, BT474, and MCF-7 cells were transfected with either empty vector (pMT) or C/EBP expression vector using the GenePORTER transfection reagent (GTS, Inc., San Diego, CA). Selection with G418 was started 48 hours after transfection to obtain stably transfected cells. Multiple monoclonal cultures were screened for zinc-inducible C/EBP expression by Western blot analysis.
Western blot analysis. Cells were placed in lysis buffer [50 mmol/L Tris-HCl (pH 7.4), 150 mmol/L NaCl, 0.5% NP40]; the resulting cell lysates were resolved on 4% to 15% gradient SDS-polyacrylamide gels and transferred to nitrocellulose membranes (Sigma, St. Louis, MO). Immunoblots were incubated with various primary antibodies followed by incubation with appropriate antirabbit or antimouse secondary IgG antibody conjugated with horseradish peroxidase (Amersham Pharmacia Biotech, Piscataway, NJ). SuperSignal West Pico substrate (Pierce, Rockford, IL) was used for detection. The following primary antibodies were used: anti-C/EBP (sc-61), anti-c-Myc (sc-764), anti-p21 (sc-817), anti-PPAR (sc-7273), from Santa Cruz Biotechnology (Santa Cruz, CA), and anti–glyceraldehyde-3-phosphate dehydrogenase from Research Diagnostics (Flanders, NJ). Western blots were stripped between hybridizations with stripping buffer [10 mmol/L Tris-HCl (pH 2.3) and 150 mmol/L NaCl].
Colony formation assay. MCF-7, BT474, MDA-MB-231, MDA-MB-468, and SKBR3 cells were split evenly into six-well plates. Cells were transfected with either pcDNA3.1 empty vector or pcDNA3.1-C/EBP and cultured under G418 selection. After 2 weeks, the colonies were stained with 0.1% crystal violet and photographed.
Cell proliferation, cell cycle analyses, and clonogenic assay. Cell proliferation was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays (Roche Diagnostics, Basel, Switzerland) according to the manufacturer's protocol. For cell cycle analyses, cells were fixed in cold ethanol; stained with 50 µg/mL propidium iodide, 1 mg/mL RNase, and 0.1% NP40; and analyzed by FACScan and CELLFit program (BD Biosciences Becton Dickinson, San Jose, CA). For clonogenic assay, 231-pMT and 231-pMT cells (1 x 103) were plated either with or without ZnSO4 (100 µmol/L) into 24-well flat-bottomed plates using a two-layer soft agar system. After 10 days of incubation, the colonies were counted and measured. All of the experiments were done at least thrice using triplicate plates per experimental point.
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Results |
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in normal breast tissue, primary breast cancers, and breast cancer cell lines. C/EBP gene expression levels were measured in 16 normal breast tissue samples, 24 primary breast cancers, and 8 breast cancer cell lines by performing real-time RT-PCR. Among the breast tumor samples, 20 of 24 (83%) showed diminished levels of C/EBP gene expression (Fig. 1). No association was noted between estrogen receptor (ER) status and C/EBP mRNA expression levels in the breast cancer samples. Three of four ER-negative cell lines showed decreased C/EBP expression, whereas no reduction was seen in the four ER-positive cell lines. These results show that the expression of C/EPB at the RNA level is strongly down-regulated in primary breast cancers.
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protein expression in primary breast cancer samples. To further explore if down-regulation of C/EBP occurs in primary breast cancer cells, we did immunohistochemical analysis of C/EBP protein expression on 37 cases of invasive sporadic primary breast carcinomas (Fig. 2; Table 2). Of the 37 cases examined, nuclear and cytoplasmic cytoplasm expression of C/EBP was noted in 26; of these, 13 showed weak staining (1+; Fig. 2D) and the remaining 13 showed strong staining (2+; Fig. 2C). Loss of expression was seen in 11 cases (30%). This loss of expression was limited to the nuclei of the cancer cells (Fig. 2E). A normal staining pattern was observed in the adjacent normal tissue in these 11 cases. Areas of ductal carcinoma in situ were noted in 14 cases. Ten samples showed positive staining, whereas four cases were negative. In all instances, the pattern of expression in ductal carcinoma in situ was reflected in the invasive cancer.
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expression. Clinical and pathologic parameters of the 11 cases of invasive carcinomas with reduced C/EBP expression were analyzed and compared with the 26 cases with no loss of expression using the Fisher's exact test. A significant correlation was found between ER/progesterone receptor and C/EBP expression (P = 0.05 for ER and P = 0.001 for progesterone receptor). These data show that C/EBP expression is down-regulated in breast cancers. Although studies showed that C/EPB has antiproliferative effects in epithelial cells, its potential growth-inhibitory properties in breast cancer have not been studied. We therefore examined the possibility that expression of C/EPB plays a role in breast cancer.
C/EBP inhibits the clonal proliferation of breast cancer cell lines. We used colony formation assays to assess the effect of C/EPB on the growth rate of breast cancer cell lines. Five breast cancer lines were transfected with either a C/EBP expression vector (pcDNA3.1-C/EBP) or an empty vector (pcDNA3.1) as control. Transfected cells were cultured in selection media for 2 weeks and then stained to determine the number of surviving colonies. C/EBP expression dramatically reduced the number and size of surviving colonies from all five breast cancer cell lines compared with empty vector-transfected controls (Fig. 3). Untransfected cells died within the 2 weeks of culture in the selection media (data not shown).
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inhibits breast cancer cell growth. To analyze the effects of C/EBP expression on cell growth, we selected three breast cancer cell lines, MDA MB 231 (ER positive), BT474 (ER-positive, overexpressing ErbB2/HER2), and MCF-7 (ER-negative) for additional studies. We stably transfected these cells with a vector containing the human C/EBP gene under the control of the zinc-inducible metallothionein promoter (pMT) as well as the control empty vector (pMT). Stable clones were selected on the basis of G418 resistance and C/EBP expression was determined by Western blot analysis (Fig. 4).
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as measured by MTT assays (Fig. 5A). Cell cycle analysis was done to clarify which phase of the cell cycle was blocked in the C/EBP overexpressing cells (Fig. 4B). The results showed that by day 4 of C/EBP induction, the pMT cell lines had an increased number of cells in the G0-G1 phase and a decreased number in the S phase of the cell cycle compared with the pMT control cells.
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expression on anchorage-independent clonal growth of MDA-MB-231 in soft agar (Fig. 5C). The 231-pMT cells formed robust colonies in soft agar both in the absence and presence of zinc. In comparison, zinc treatment of the 231-pMT cells resulted in markedly decreased clonal growth both in number (52%) and size of the colonies (data not shown), suggesting that overexpression of C/EBP inhibited the transforming potential of the MDA-MB-231 cells.
C/EBP induces up-regulation of p21(WAF1/CIP1) and down-regulation of c-myc. To begin elucidating the molecular mechanism by which C/EBP inhibits proliferation of breast cancer cells, the pMT and pMT cell lines were cultured in the presence of zinc and expression level of several cell cycle–related proteins was determined by Western blot analysis. Induction of C/EBP up-regulated the expression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) and repressed the expression of c-myc (Fig. 6).
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induces expression of PPAR and the breast epithelial marker, maspin. C/EBP has been shown to mediate not only growth arrest but also terminal differentiation in different cell types (12, 15, 16, 19). We therefore examined whether C/EBP can induce the expression of peroxisome proliferator-activated receptor (PPAR), previously implicated in breast cancer differentiation (29, 30), and maspin, a known breast epithelial marker. The pMT and pMT breast cancer cells were cultured in the presence of zinc, and PPAR and maspin expression levels were measured by real-time RT-PCR. Induction of C/EBP increased the mRNA levels of PPAR by 6-, 3-, and 4-fold in the 231-pMT, BT474-pMT, and MCF-7-pMT cells, respectively, compared with mRNA levels in the control cells transfected with empty vector (pMT) and untransfected cells (Fig. 7A). Similarly, expression of C/EBP up-regulated the levels of maspin mRNA by 7- and 11-fold in the 231-pMT and BT474-pMT cells, respectively, compared with control cells (Fig. 7A). In contrast, expression of C/EBP did not change maspin levels in the MCF-7-pMT cells; maspin levels were already prominent in wild-type, well-differentiated MCF-7 breast cancer cells. Western blot analysis showed that PPAR protein levels were also induced in the 231-pMT, BT474-pMT, and MCF-7-pMT cells (Fig. 7B).
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Discussion |
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is down-regulated in breast cancer and has growth inhibitory properties in mammary epithelial cells. In animal models, C/EBPs are differentially expressed during mammary gland development and during pregnancy and lactation, suggesting a role for these transcription factors in the function and differentiation of the mammary gland (4, 5). Consistent with the antiproliferative phenotype of C/EBP, it is weakly expressed before and during pregnancy, when proliferation takes place, and is elevated during lactation in terminally differentiated mammary cells. In the recent past, several genomic profiling studies [such as Perou et al.'s (31) and van 't Veer et al.'s (32) studies] were done on large numbers of primary human breast carcinoma samples. These studies do not show significant association between C/EBP mRNA expression and various clinical parameters, including ER status. Similarly, in our study, no correlation was noted between C/EBP mRNA levels and ER status in primary breast cancer samples. We did, however, find reduced expression of C/EBP mRNA in ER-negative breast cancer cell lines, and immunohistochemical studies showed that primary tumor samples with either low or undetectable levels of C/EBP protein were predominantly ER negative. Various models involving both transcriptional and posttranscriptional mechanisms have been proposed to account for disruption of C/EBP function in cancer cells. Interestingly, our immunohistochemical analysis showed cytoplasmic as well as nuclear staining for C/EBP. Cytoplasmic localization of C/EBP might contribute to inactivation of this transcription factor in breast cancer cells.
Reestablishment of C/EBP expression in breast cancer cell lines resulted in reduced growth in liquid culture, inhibition of clonogenic growth, and G0-G1 cell cycle arrest. The growth and differentiation regulatory functions of C/EBP are complex and versatile. Data now suggest that, in addition to its activity as a transcription factor, C/EBP can modulate growth arrest and differentiation by protein-protein interactions with cell cycle regulatory proteins (2, 20–27). Consistent with previous reports, we found that ectopic expression of C/EBP in breast cancer cells increased p21(WAF1/CIP1) and decreased c-myc protein levels. These results suggest that different pathways may be involved in C/EBP-mediated growth arrest in breast cancer cells. Further studies will determine which mechanisms are significant in C/EBP-dependent growth inhibition of breast cancer and other cancer epithelial cell malignancies. In adipocytes, C/EBP and the ligand-stimulated transcription factor PPAR positively regulate each other's expression (33). Recent reports have shown that PPAR ligands may promote differentiation and/or regression of mammary tumors (29, 30). Here, we show that expression levels of PPAR as well as the breast epithelial marker, maspin, were up-regulated in the C/EBP-expressing cells, suggesting that these cells acquire a more differentiated, less malignant phenotype. In accordance with earlier studies, our data reinforce a critical role for C/EBP in regulating the balance between uncommitted, proliferating cells, and differentiated, growth-arrested cells.
In summary, we found down-regulation of C/EBP mRNA and protein levels in breast tumors. Restoring C/EBP expression in a breast cancer cell line resulted in inhibition of growth associated with a G0-G1 cell cycle arrest. These results suggest that C/EBP is involved in mammary carcinogenesis and that its aberrant expression may be important in breast cancer.
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Footnotes |
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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.
Note: S. Gery and S. Tanosaki contributed equally to this work. H.P. Koeffler is a member of the Jonsson Comprehensive Cancer Center and the Molecular Biology Institute, University of California at Los Angeles, and holds the endowed Mark Goodson Chair of Oncology Research at Cedars-Sinai Medical Center/University of California at Los Angeles School of Medicine.
Received 12/20/04; accepted 2/ 1/05.
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1,000 cells were counted on day 10. Experiments were done in triplicate and repeated twice. Columns, mean of a representative experiment; bars, SD.
