[CANCER RESEARCH 63, 560–566, February 1, 2003]

Advances in Brief

Loss of BRG1/BRM in Human Lung Cancer Cell Lines and Primary LungCancers: Correlation with Poor Prognosis1

David N. Reisman,2 Janiece Sciarrotta, Weidong Wang, William K. Funkhouser, and Bernard E. Weissman3

Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7525 [J. S., W. K. F., B. E. W.]; Laboratory of Genetics,National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224 [W. W.]; and Lineberger Comprehensive Cancer Center, University of North Carolina,Chapel Hill, North Carolina 27599-7295 [D. N. R., B. E. W.]

Abstract

A role for the SWI/SNF complex in tumorigenesis based on its require-ment for retinoblastoma induced growth arrest and p53-mediated tran-scription and the appearance of tumors in SWI/SNF-deficient mice. Inaddition, Western blot data have shown that the SWI/SNF ATPase sub-units cell, BRG1 and BRM (BRG1/BRM), are lost in �30% of humannon-small lung cancer cell lines. To determine whether loss of expressionof these proteins occurs in primary tumors, we examined their expressionin 41 primary lung adenocarcinomas and 19 primary lung squamouscarcinomas by immunohistochemistry. These analyses showed that 10%of tumors show a concomitant loss of BRG1 and BRM expression. More-over, patients with BRG1/BRM-negative carcinomas, independent ofstage, have a statistically significant decrease in survival compared withpatients with BRG1/BRM. This report provides supportive evidence thatBRG1 and BRM act as tumor suppressor proteins and implicates a rolefor their loss in the development of non-small cell lung cancers.

Introduction

SWI/SNF is a multimeric chromatin remodeling complex importantfor gene regulation. Like other proteins involved in gene regulation,the SWI/SNF complex is a potential target for disruption duringneoplastic progression. Investigations into the chromosomal aberra-tions in 22q11.2 region led to the discovery of the SWI/SNF compo-nent, SNF5/INI1/BAF47, as a tumor suppressor gene in rhabdoidtumors, rhabdomyosarcomas, and choroid plexus carcinomas (1–3).The finding that SNF5/INI1/BAF47 heterozygous mice develop tu-mors that closely resemble human rhabdoid tumors further supportsthis notion (4, 5). In yeast, the functions of the complex require thefunctional integrity of the subunits, and loss of any one component issufficient to alter the function of the complex (6). Thus, disruption ofthe SWI/SNF complex by the loss of other subunits may also beassociated with human tumorigenesis. To this end, investigations haveshown an evolving role for the mutually exclusive SWI/SNFATPases, BRM (Brahma) and BRG1 (BRM-related gene 1), ingrowth control and tumorigenesis. Transgenic heterozygous BRG1mice (BRG1�/�) form s.c. tumors resembling breast cancer (7).Although BRM null transgenic mice (BRM�/�) do not form tumors,the loss of expression of BRM causes cells to have an altered prolif-eration and impaired cell cycle control (8). Moreover, the BRG1 andBRM interact with key regulatory proteins, including RB4 protein,p53, p107, p130 (RB2), BRCA1, and �-catenin (2, 9). Specifically,

BRG1 protein is required for RB-induced growth inhibition, p53-mediated transcription and BCRA1-controlled gene expression (10–12). Thus, the loss of BRG1 and BRM expression should impact on amultitude of growth regulatory pathways. These data provide a ra-tionale for BRG1 and BRM to function as tumor suppressor proteins.

Although these and other data appear compelling, establishingBRG1 and BRM as bona fide tumor suppressors also requires dem-onstrating their loss of expression in primary tumors. Therefore, basedon data showing loss of BRG1 and BRM expression in �30% ofhuman NSCLC cell lines and published data showing loss of het-erozygosity surrounding the BRG1 and BRM loci in human lungcancers (13) we conducted immunohistochemical staining for BRG1and BRM on 60 NSCLC samples taken from patients that underwentcurative resections for stage I–IIIA tumors. We observed loss ofBRG1/BRM expression in 6 of 60 tumor samples (�10%), suggestingthat BRG1/BRM loss in tumor cell lines does not arise as a tissue-culture artifact. Consistent with cell line data, loss of BRG1 expres-sion occurred concomitantly with loss of BRM expression. Clinically,loss of BRG1/BRM expression in NSCLC was associated with asignificantly worse patient survival compared with the survival ofpatients with BRG1/BRM-positive tumors. These data additionallysupport that BRG1/BRM act as tumor suppressor proteins and thatloss of function of these proteins may potentially impact the clinicaloutcome of NSCLC.

Materials and Methods

Immunohistochemical Staining. Normal human tissue and pairedNSCLCs were collected from University of North Carolina archives, and 5-�msections were cut and mounted on Probe On Plus slides (Fisher Scientific).After deparaffinization in xylene, slides were rehydrated and placed in runningwater. Slides were placed in a MicroProbe slide holder (Fisher Scientific), andthe appropriate antigen retrieval buffer was applied, BRG1 in AR-10 (Bio-Genex) and BRM in Citra (BioGenex). All slides were then placed in a Blackand Decker steamer for 30 min and allowed to cool for 20 min. After multiplerinsing in Automation Buffer (Biomeda), endogenous peroxidase wasquenched using a 3% solution of hydrogen peroxide. Excess protein was thenblocked using normal goat serum (BioGenex), and the sections were thenexposed to the primary antibodies, BRG1 1:1000 (a gift from Pierre Chambon)or BRM 1:50 (Transduction Laboratories) for 30 min at 37°C. After rinsing inAutomation buffer, slides were then placed in the secondary antibody (Bio-Genex Super Sensitive Multi Link) for 7 min at 37°C, rinsed in AutomationBuffer, and then incubated in the label (BioGenex Super Sensitive HRP) for 7min at 37°C. After again rinsing in Automation Buffer, detection of theantibody/antigen complex was visualized using 3,3� diaminobenzidine. Slideswere then lightly counterstained in Mayer’s hematoxylin, rinsed, dehydrated,cleared, and mounted.

Tumor Samples. Tumor samples banked at the University of North Caro-lina from 1997–1999 were randomly selected. The specimens were derivedfrom patients with stage I–IIIA NSCLC. Internal Review Board approval wasobtained before our analysis.

Received 9/20/02; accepted 12/13/02.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 with18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported, in part, by NIH Grant CA91048 (to B. E. W.). D. N. R.received support from NIH Grant T32CA09156 and the Kempner Foundation, Universityof Texas Medical Branch, Galveston, TX.

2 Present address: Division of Hematology/Oncology Department of Medicine, Uni-versity of Michigan, Ann Arbor, MI 48108.

3 To whom requests for reprints should be addressed. Phone: (919) 966-7533; Fax:(919) 966-9673; E-mail: weissman@med.unc.edu.

4 The abbreviations used are: RB, retinoblastoma; NSCLC, non-small cell lung cancer.

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Statistical Analyses. The Kaplan-Meier (or product limit) method wasused to estimate the survivorship function. We used the log-rank test to identifypossible differences between estimated survival curves. All analyses were per-formed with SAS statistical software, version 8.2, from SAS Institute (Cary, NC).

Results

To determine whether SWI/SNF complex members other thanINI1/SNF5/BAF47, a known tumor suppressor gene, were lost inhuman carcinomas, we screened a variety of human cell lines derivedfrom different primary carcinomas (14). We found that loss of ex-pression of BRM and BRG1 appears more frequently than the loss ofother complex subunits, occurring in 10% (8 of 80) of human tumorcell lines (14). In these cell lines, the down-regulation of BRG1occurred concomitantly with down-regulation of BRM (15). Also,four of eight BRG1/BRM-deficient cell lines were derived from lungadenocarcinomas, representing 33% (4 of 12) of NSCLCs overall.Similarly, Wong et al. (16) showed BRG1 has been mutated in 14%(2 of 14) of NSCLC cell lines and 10% (18 of 180) of human tumorcell lines using high throughput DNA sequencing. Subsequent West-ern blotting analysis of these cell lines showed that only the lungcancer cell lines (A427 and H1299) harboring BRG1 mutations hadlow to no expression of both BRG1 and BRM (17). Taken together,these cumulative data show that loss of BRG1 and BRM expressionoccurs in �30% (6 of 20) of human lung cancer cell lines (Table 1).

Primary Human NSCLC Show Reduced or Absent BRG1 andBRM Expression. To establish that loss of BRG1/BRM occurs inprimary tumors and does not arise from the establishment of the celllines, we examined the expression of BRM and BRG1 in 41 primarylung adenocarcinoma cancers and 19 primary lung squamous cellcarcinomas by immunohistochemistry. By using a BRG1-specificantibody, we first detected BRG1-negative tumors. Staining the sameBRG1-negative tumors with a second antibody that recognizes aconserved shared BRG1/BRM epitope, allowed us to unambiguouslydetermine the presence or absence of BRM expression. In addition,when staining was not detected with this second antibody, it alsoconfirmed that these tumors were negative for BRG1.

Using the BRG1 specific antibody, we detected loss of BRG1expression in 6 of 60 tumors (�10%; Figs. 1, A–F, and 2). These 6tumors also showed no positive signal with the second antibodyshowing that neither BRG1 nor BRM expression was present (Figs. 1,

G–L, and 2). Moreover, these tumors did not show a continuum ofstaining with either of these antibodies such that the positively stainedtumors are distinctly grouped from the negatively stained tumors(Fig. 2).

The other 54 tumors stained positively with both antibodies, indi-cating they expressed at least BRG1 protein. We previously showedthat both antibodies specifically recognize BRG1 and BRG1/BRM,respectively (15). Of the 6 BRG1-negative tumors, 3 were uniformlydevoid of either BRG1 or BRM expression, whereas the other 3tumors had focal and minimally detectable staining. The loss ofBRG1/BRM expression in these tumors was not attributable to stain-ing irregularities because the immunohistochemistry on these sampleswas repeated to confirm the results, and each sample showed internalpositive control staining (normal bronchial epithelial and infiltratinglymphocytes).

Although we have previously observed that the loss of expressionof both BRG1 and BRM appear limited to adenocarcinoma cell lines(15), we also found reduced or absent BRG1 and BRM expression inadenocarcinomas (3 of 41) as well as squamous cell carcinomas (3 of19; Fig. 2A). Interestingly, two of these latter carcinomas are adeno-squamous type, and loss of BRG1/BRM expression was noted in thearea of adenocarcinoma morphology as well as in the area of squa-mous carcinoma morphology. These results suggest that loss of BRG1and BRM may not be restricted to adenocarcinomas, as suggested byour original cell line data. Consistent with our previous studies,tumors demonstrated concomitant loss of BRG1 and BRM expression(Fig. 2A). However, because the second monoclonal antibody (Trans-duction Laboratories) detects both BRG1 and BRM proteins (Ref. 15;Reisman, unpublished data), we cannot determine whether any of theBRG1-positive tumor samples lack only BRM expression.

Loss of BRM/BRG1 Correlates with a Worse Prognosis inNSCLCs. We compared the survival of the 6 patients who hadBRG1/BRM-negative tumors to the 54 patients with BRG1-positivetumors (Fig. 3, B and D). During a median 36-month follow-upperiod, the BRG1-positive patients with stage I, II, and III disease hada survival of 79, 66, and 44%, respectively, consistent with previouslypublished data (Fig. 3; Ref. 18). However, the patients with BRG1-negative tumors had 0% survival during this period (Fig. 3D). TheKaplan-Meier curves show this survival difference between patientswith BRG1-positive and BRG1-negative tumors (Fig. 3B). Lung

Table 1 Expression of BRG1 and BRM in human lung cancer cell lines

A total of 20 human NSCLC lines have been screened by sequencing for BRG1 mutations and/or western blotting for BRM and BRG1 protein expression. Six human NSCLCacell lines (rows 1–4, 17, 19) (�30%) have concomitant significantly reduced to no expression of BRG1 and BRM by Western blotting. Wong et al. (15) found mutations in the BRG1gene in two of these cell lines (A427 and H1299). ND, not determined.

Cell line BRG1 BRM BRG1 mutation Ref.

1 NCI-H1573 Low Low ND 162 NCI-H23 Low Low ND Reisman-unpublished3 NCI-H522 Neg Neg ND 164 NCI-H125 Low Low ND 165 A549 Pos Pos ND Reisman-unpublished6 Calu-3 Pos Pos ND Reisman-unpublished7 NCI-H441 Pos Pos No Reisman-unpublished, 158 SK-Lu Pos Pos ND Reisman-unpublished9 Calu-6 Pos Pos No Reisman-unpublished, 15

10 676-B Pos Pos ND Reisman-unpublished11 NCI-H2122 ND ND No 1512 NCI-H774 ND ND No 1513 SK-MES-1 ND ND No 1514 NCI-H1155 ND ND No 1515 NCI-H596 ND ND No 1516 NCI-H292 ND ND No 1517 A427 Neg Neg Yes 15,1718 NCI-H460 ND ND No 1519 NCI-H1299 Low Low Yes 15,1720 Calu-1 ND ND No 15

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cancer patients with stage I, II, and IIIA disease have progressivelyworse survival despite best therapy (curative surgical resection). Al-though the patients with BRG1-negative tumors had primarily stage I(2 of 6) and stage II (3 of 6) disease, they had a statistically worse

survival (P � 0.03) than patients with the clinically more advancedstage IIIA (BRG1 positive) tumors (Fig. 3C). This difference insurvival is not because of difference in treatment or therapies as all 60patients were treated with surgery alone without any neoadjuvant or

Fig. 1. BRG1 and BRM expression in primary NSCLCs. Forty-one adenocarcinomas and 21 squamous cell carcinomas were stained for BRG1 expression using a BRG1-specificmonoclonal antibody. Six tumors were devoid of BRG1 expression, whereas the normal bronchial epithelium and/or infiltrating lymphocytes within these samples showed specificnuclear staining (as illustrated in the 3 tumors B, D, and F). In comparison, 54 of the tumors showed preferential nuclear staining as illustrated in A, C, and E. The same 6 tumors,which were devoid of BRG1 expression, were stained with a BRM/BRG1 antibody that detects both proteins. These tumors were also found to have minimal to no BRM expressionas illustrated in the 3 tumors H, J, and L. Internal positive controls can be seen in these samples [bronchus (J) and lymphocytes (H and L)]. The other 54 tumors show specific nuclearstaining as exemplified in tumors shown in G, I, and K.

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adjuvant therapies. As might be expected, patients with BRG1-negative NSCLC also had worse survival than patients with stage-matched BRG1-positive NSCLC.

Discussion

SWI/SNF complex subunits were first implicated in tumorigen-esis when INI1/hSNF5/BAF47 was recognized as a tumor suppres-

sor. The expression of this protein is lost in pediatric rhabdoidtumors and certain central nervous system tumors secondary toinactivating mutations and gene deletions (1, 2, 19). We show thatlike INI1/hSNF5/BAF47, the SWI/SNF ATPase subunits, BRG1and BRM proteins, are also lost in a subset of primary humantumors. This finding, together with transgenic animal data showingthat loss of BRG1 is tumorigenic and that BRM is involved in

Fig. 1. Continued

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proliferation, supports that BRG1 and BRM are tumor suppressorproteins. Mechanistically, cell line data additionally supports thisconcept by showing that BRG1 and BRM expression is required forRB-mediated growth inhibition (12, 15, 20). Thus, the loss of BRG1/BRM may serve to abrogate the RB pathway similar to the loss of p16and/or RB function in human tumors.

The loss of function of the SWI/SNF complex will likely pro-duce major phenotypic changes within tumors because of its in-teraction and requirement in many signal transduction pathways inaddition to the RB pathway. BRG1 and BRM have been shown tointeract with cyclin E, Myo-D, p53, p107, and p130 (RB2; Ref. 2,11, 21, 22). Their function is also required for the function ofestrogen, glucocorticoid, progesterone, and retinoic acid receptors(19). Another affect of BRG1/BRM loss may come from theSWI/SNF complex’s contribution, via BAF60a, to the induction ofAP1 responsive genes (23). The number of genes actually regu-

lated by the SWI/SNF complex is at least 80 and in yeast theSWI/SNF complex regulates 5–7% of the yeast genome (24). Thus,the broad changes in the signaling pathways that must occur withloss of BRG1/BRM must have an impact on the tumor phenotype.Our data suggest that this loss may be an important indicator of apatient’s overall survival.

As with human cancer cell lines, primary tumors appear to haveconcomitant loss of both BRG1 and BRM protein expression. Becauseexperiments with human tumor cell lines show that BRG1 and BRMhave redundant functions (12, 15, 25), their concomitant loss may berequired to completely inactivate the SWI/SNF complex. However,biochemical analyses by several groups have shown that BRM andBRG1 are contained in different complexes that, in turn, have appar-ently different biochemical functions (26, 27). Whether the concom-itant loss of BRG1 and BRM expression is required to abrogateseparate SWI/SNF functions or occurs because BRG1 and BRM share

Fig. 2. Comparison of BRG1 and BRM expres-sion in lung adenocarcinomas and lung squamouscell carcinomas. A shows quantitative expression(staining intensity) of BRG1 and BRM in lungadenocarcinomas and lung squamous cell carcino-mas. Two independent pathologists evaluated theslides. A value for each sample was derived byestimating the percentage of cells (in decade incre-ments, 0–100%) showing nuclear immunoreactiv-ity and then multiplying by their average intensity(range, 0–3; A). This product is referred to asIntensity. B and C show the distribution of BRG1and BRM/BRG1 staining when intensity is graphedversus percentage of staining. Adenocarcinomasand squamous cell carcinomas are denoted bysquare and diamond symbols, respectively. A–Cshow that 6 tumors show little or no staining witheither BRG1 or BRM/BRG1 antibodies, whereasthe other 54 tumors show �50% staining; the de-ficient tumors are bolded within Table A. Becausethe data are incremental, there is overlap of somedata points and thus not all symbols are visualized.

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redundant functions important for tumorigenesis, warrants additionalinvestigation.

Acknowledgments

We thank Dr. Dominic Moore for his assistance with the statistical analysis.We also thank Dr. Moshe Yaniv and Dr. Christian Murchardt for their gift ofthe BRM specific antisera, and Dr. Pierre Chambon for his gift of the BRG1monoclonal antibody.

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Fig. 3. Loss of BRG1 and BRM expression in NSCLC correlates with reduced survival. To determine whether loss of BRG1/BRM expression was clinically significant, the survivalof patients with BRG1/BRM-positive tumors (N � 54) was compared with the survival of patients with BRG1/BRM-negative tumors (N � 6). These patients were stage I (n � 37),stage II (n � 13), and stage IIIA (n � 10) at diagnosis and were treated with intent to cure with surgery (A). The median follow-up was 36 months from years 1997 to 2002. TheKaplan-Meier Curve in Fig. 3B shows statistically significant differences (P � 0.0001) in the survival of patients with BRG1/BRM-positive tumors compared with patients withBRG1/BRM-negative tumors. The patients with BRG1/BRM-negative tumors were all deceased within 29 months. Although these two groups were not balanced with respect to stage,which in turn correlates with survival, the patients with BRG1/BRM-negative tumors (primarily stages I and II) have statistically worse survival (P � 0.03) when compared with thepatients with BRG1/BRM-positive stage IIIA tumors (Kaplan-Meier Curves Graph 3C). The 1-year, 2-year, 3-year, and median survival of these two groups are shown in D.

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2003;63:560-566. Cancer Res   David N. Reisman, Janiece Sciarrotta, Weidong Wang, et al.   Primary Lung Cancers: Correlation with Poor PrognosisLoss of BRG1/BRM in Human Lung Cancer Cell Lines and

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