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[Cancer Research 61, 7739-7742, November 1, 2001]
© 2001 American Association for Cancer Research

Advances in Brief

The Presence of Single Nucleotide Instability in Human Breast Cancer Cell Lines1

Naoko Watanabe, Eriko Okochi, Masataka Mochizuki, Takashi Sugimura and Toshikazu Ushijima2

Carcinogenesis Division, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045 [N. W., E. O., T. S., T. U.], and Division of Organic and Bio-organic Chemistry, Kyoritsu College of Pharmacy, Shiba-koen 1-5-30, Minato-ku, Tokyo 105-8512 [N. W., M. M.], Japan


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
The presence of single nucleotide instability, an increase of spontaneous point mutation rates (MR: number of mutations per cell division) without microsatellite instability, was demonstrated previously in two rat mammary carcinoma cell lines. In this study, spontaneous point MRs were analyzed in human breast cancer cell lines by the fluctuation test using the hypoxanthine-guanine phosphoribosyltransferase (hprt) marker gene. MRs obtained for six breast cancer cell lines, MCF-7, ZR-75-1, T-47D, MDA-MB-231, MDA-MB-468, and BT-474, all of which were proficient in G/T mismatch binding and reported to be negative for microsatellite instability, were 7.6, 4.6, 6.3, 2.2, 5.6, and 19 x 10-7 mutations/hprt/cell division. Those in normal human mammary epithelial cells and in a colon cancer cell line with proficient mismatch repair, SW480, were 1.6 and 1.4 x 10-7 mutations/hprt/cell division, respectively. These findings showed that single nucleotide instability was also present in five of the six human breast cancer cell lines and strongly indicates it has important roles in human and rat mammary carcinogenesis.


   Introduction
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 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
Genetic instabilities play a wide role in human carcinogenesis and have traditionally been classified into two categories, according to their main target sequences (1 , 2) . Chromosomal instability is characterized by frequent chromosomal losses and gains and is caused mainly by mutations of genes involved in appropriate partitioning of chromosomes during mitosis, such as MDA2 and BUB1 (3) . MSI3 is characterized by frequent alterations of the numbers of repetitive sequences and is caused mainly by mutations of mismatch repair genes, such as MSH2, MLH1, and PMS2 (4, 5, 6) . Inactivation of the mismatch repair system is known to cause mutations not only in microsatellites but also in random sequences (7 , 8) , e.g., mice deficient for MSH2 displayed 5–15-fold increases of mutations accumulated in normal tissues (8) . MSI is often observed in colon, stomach, and pancreatic cancers but infrequently in breast cancers (9 , 10) .

From rat mammary carcinomas induced in lacI-transgenic rats by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (11) , we established previously two mammary carcinoma cell lines, PhIP12-1 and PhIP7-4, which lacked MSI (12) . Using the lacI transgene and the endogenous hprt gene as markers, spontaneous point MRs were measured by the fluctuation test of Luria and Delbrück (13) . For both the exogenous and endogenous genes, MRs were shown to be increased at 6- and 8-fold in PhIP12-1 and PhIP7-4, respectively (12) . Analysis of the types of mutations revealed that A:T to C:G transversions, which are rarely induced by mutagens or observed as "spontaneous mutations," were present at 24–25% in the two cell lines. The A:T to C:G transversions were observed at 16–24% in the lacI transgene in the primary carcinomas of the two cell lines but infrequently in their surrounding noncancerous tissue (11) . This indicated that the increase of spontaneous point MRs without involvement of MSI was present in the primary carcinomas. We termed the increase of spontaneous point MRs without involvement of MSI as SNI. The SNIs observed in PhIP12-1 and PhIP7-4 were characterized by the high frequency of A:T to C:G transversions.

The low incidence of MSI in human breast cancers and the presence of SNI in rat mammary carcinomas suggest that SNI is also present in human breast cancers. In this study, we analyzed spontaneous point MRs of the hprt gene in six human breast cancer cell lines: MCF-7, ZR-75-1, T-47D, MDA-MB-231, MDA-MB-468, and BT-474. For each cell line, we performed 24 parallel cultures from 102 cells to 106 cells and analyzed all of the mutants produced during the cultures. All of these cell lines were reported to be negative for MSI by analyzing mutations in four single/trinucleotide repeats (10) , and we additionally confirmed that they were capable of G/T mismatch binding by a gel shift assay.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Cell Lines.
Human breast cancer cell lines MCF-7, ZR-75-1, T-47D, MDA-MB-231, MDA-MB-468, and BT-474 and colon cancer cell lines SW480 and LoVo were purchased from the American Type Culture Collection (Manassas, VA). These cell lines were grown in RPMI 1640 (Life Technologies, Inc., New York, NY) supplemented with 10% fetal bovine serum (JRH Bioscience, San Antonio, TX), penicillin, streptomycin (Life Technologies, Inc.), and amphotericin B (Fungizone; Life Technologies, Inc.). Human colon cancer cell line DLD-1 was obtained from Japan Health Sciences Foundation (Osaka, Japan) and grown in Ham’s F-12 (Life Technologies, Inc.) supplemented with 10% fetal bovine serum, penicillin, and streptomycin. HMEC was purchased from Clonetics (Walkersville, MD) and was grown in mammary epithelial basal medium (Clonetics) supplemented with bovine pituitary extract, gentamicin sulfate, amphotericin B, epidermal growth factor, insulin, and hydrocortisone (Clonetics).

Analysis of Doubling Time and Plating Efficiency.
Cells in their log-phase growth were seeded at 3 x 104 cells per 6-cm dish. Cells in three dishes were harvested at days 1, 2, 3, 4, 5, 6, and 7 days, and the number of cells in each dish was counted. Plating efficiencies were calculated by plating cells at a density of 1–3 cells/well in a 96-well plate and counting the number of positive wells and the number of colonies in positive wells.

Analysis of MRs.
In advance, each cell line was treated with various concentrations of 6TG (Sigma Chemical Co., St. Louis, MO) at 0.2, 0.5, 1, 1.5, and 3 µg/ml, and the lowest concentration that killed all of the cells within a week was adopted for the 6TG selection. The concentration adopted was 1.5 µg/ml for HMEC and the six breast cancer cell lines and 0.5 µg/ml for the colon cancer cell line, SW480.

Cells in their log-phase growth were seeded at 102 cells in a well of a 96-well plate. The cells were serially transferred to a well of a 24-well plate, a 6-cm dish, and a 10-cm dish and cultured until subconfluence in the 10-cm dish. The cells in the 10-cm dish were collected, counted, and divided into the 96 wells of a 96-well plate. After the plating (24 h), 6TG was added to the medium, and the number of hprt mutants was counted 6–8 weeks later (14) . For each cell line, 24 replicate experiments were performed. The MR was calculated based on the equation (8) of Luria and Delbrück (13) . MF was calculated as the number of mutants per the final number of cells.

Sequencing Analysis of Mutants.
cDNA was directly synthesized from colonies of hprt mutants using a Cells-to-cDNA kit (Ambion, Inc., Austin, TX). The coding region was amplified by PCR with primers H9F: 5'-GCGCGCCGGCCGGCTCCGTT-3' and AS685: 5'-GGCGATGTCAATAGGACTCCAGATG-3' (Ref. 15 ; Mg2+ 1.5 mM, annealing at 64°C). The PCR product was directly cycle-sequenced using Cy5-labeled primers, H11F: 5'-GCCGGCCGGCTCCGTTATGG-3' and AS661: 5'-TCAACTTGAACTCTC-3' (15) using Thermo Sequenase (Amersham-Pharmacia) and an ALFexpress automatic DNA sequencer (Amersham-Pharmacia).

Gel Shift Assay.
A probe with G/T mismatch was prepared by annealing of oligonucleotides, MR1 (5'-CTATGCTAAATTCCCGGGGATCCGTCGACCTGCAGCCAAGCT-3') with MR3 (5'-TCGAAGCTTGGCTGCAGGTTGACGGATCCCCGGGAATT-3'), and by filling in the 5'-protruding ends with FluoroLink Cy5-dCTP (Amersham-Pharmacia) and Klenow fragment (Amersham-Pharmacia). A probe without mismatch was prepared by annealing of MR1 and MR2 (5'-TCGAAGCTTGGCTGCAGGTCGACGGATCCCCGGGAATT-3') and by filling in the ends. Nuclear protein extract (10 µg) was mixed with Cy5-labeled probe (10 ng), and the sample was run in a 6% polyacrylamide gel containing 5% glycerol. Bands were visualized using the Storm Imaging System (Amersham-Pharmacia). Unlabeled competitors with a G/T mismatch were prepared by annealing of MR1 and MR3 and of MR7 (5'-CTATGCTACAGGTATCCCGCAATCTCGACTAGCGGCACTCGG-3') and MR8 (5'-TCGACCGAGTGCCGCTAGTTGAGATTGCGGGATACCTG-3').


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Growth Curve of Cell Lines.
The average doubling time for MCF-7, ZR-75-1, T-47D, MDA-MB-231, MDA-MB-468, BT-474, HMEC, and SW480 were 30.2 ± 0.7, 27.6 ± 0.7, 31.1 ± 0.6, 28.1 ± 1.2, 29.9 ± 0.5, 28.3 ± 0.6, 122 ± 4.2, and 29.8 ± 0.3 h (mean ± SE), respectively. HMEC showed approximately a four times slower growth compared with the six breast and one colon cancer cell lines. The plating efficiencies were 79 ± 3, 86 ± 4, 76 ± 5, 72 ± 1, 76 ± 2, 78 ± 6, 72 ± 1, and 85 ± 4% (mean ± SE), respectively. All of the cell lines used for this study showed similar plating efficiencies.

MRs in the Cell Lines.
For the six breast cancer cell lines, HMEC, and the colon cancer cell line, SW480, all of the mutants in the 24 parallel cultures were counted and collected (Table 1)Citation . The MRs obtained for MCF-7, ZR-75-1, T-47D, MDA-MB-231, MDA-MB-468, BT-474, HMEC, and SW480 were 7.6, 4.6, 6.3, 2.2, 5.6, 19, 1.6, and 1.4 x 10-7 mutations/hprt/cell division, respectively (Fig. 1)Citation . The MFs of these cell lines were 2.2 ± 0.2, 1.2 ± 0.2, 1.7 ± 0.3, 0.22 ± 0.1, 0.53 ± 0.1, 6.5 ± 0.1, 0.18 ± 0.11, and 0.11 ± 0.06 x 10-6 mutants/cell, respectively (Table 1)Citation .


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  		Table 1 hprt MFs, and MRs in six breast cancer cell lines, HMEC, and a colon cancer cell line

 


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  		Fig. 1. hprt MRs in six human breast cancer cell lines, HMEC, and a colon cancer cell line, SW480.

 
Mutational Spectra in the Cell Lines.
All of the mutants obtained other than in BT-474 (total 154), and 44 of the 113 mutants obtained from BT-474, were sequenced. A detailed list of mutants obtained is provided at our Web site.4 When mutants of the same type at the same position were obtained from one culture, they were counted as one mutation. The sequencing of 198 mutants identified 192 mutations in eight cell lines. These mutations were classified by their mutational types (Table 2)Citation .


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  		Table 2 Classification of hprt mutations

 
Gel Shift Assay.
The nuclear protein extracts from the six breast cancer cell lines, HMEC, and SW480 were capable of binding to a probe with a G/T mismatch (Fig. 2)Citation . The binding was competed for by its cold competitor and also by another competitor that had a G/T mismatch and surrounding sequence unrelated to that of the probe. In contrast, two colon cancer cell lines with MSI, LoVo with a mutation of hMSH2, and DLD-1 with mutations in G/T mismatch binding protein and in DNA polymerase {delta} (7) were deficient in G/T mismatch binding. These showed that the six breast cancer cell lines used in this study were capable of G/T mismatch binding and indicated that they would lack MSI.



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  		Fig. 2. G/T mismatch-binding capacity of the six breast cancer cell lines. Nuclear protein extract of the six breast cancer cell lines, HMEC, SW480, LoVo, and DLD-1 was mixed with probe without a G/T mismatch (Probe 1; Lanes 1 and 2) or that with a mismatch (Probe 2; Lanes 3–9) and run in a gel. To confirm specific binding to a G/T mismatch, a cold competitor with the same sequence with the probe (a, Lanes 5 and 6) or a competitor with a G/T mismatch and a surrounding sequence unrelated to the probe (b, Lanes 8 and 9) was added in increasing amounts. Whereas LoVo (MSH2 mutant) and DLD-1 (double mutant for G/T mismatch binding proteins and DNA polymerase {delta}) did not show shifted bands, the six breast cancer cell lines, HMEC, and SW480 (negative for MSI) showed shifted bands that were competed for by both competitors.

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
Five of the six breast cancer cell lines showed 2.9–12-fold increases in the MRs of the hprt gene, compared with the normal mammary epithelial cell line, HMEC, and the colon cancer cell line, SW480. The breast cancer cell lines and SW480 were shown to be proficient in G/T mismatch binding, which ruled out deficiency in at least hMSH2 and G/T mismatch binding protein (16) . The cell lines are also reported to lack MSI (10 , 15) . From these, it can be concluded that the five breast cancer cell lines had SNI, an increase in spontaneous point MR without MSI. Considering that chromosomal instability and MSI play only minor roles in human breast cancers (10 , 17) , it was suggested that SNI could be involved in a wide range of human breast cancers. Although the growth of HMEC was four times slower than the breast cancer cell lines, the colon cancer cell line negative for SNI, SW480, showed a growth speed comparable with the SNI-positive breast cancer cell lines. Therefore, an argument that a "too rapid" growth of cells does not allow them to correct mismatch and other errors produced during DNA replication and cause apparent SNI can be ruled out.

Among the breast cancer cell lines with SNI, the frequency of A:T to C:G transversions, which was characteristic in the rat mammary carcinoma cell lines with SNI (12) , was relatively high in MCF-7 (6 of 50) and T-47D (3/31) and low in BT-474 (1 of 43). The high frequency of A:T to C:G transversions in the two cell lines suggested that a common molecular abnormality(ies) is involved in SNI observed in MCF-7 and T-47D and in SNI in the two rat cell lines. A:T to C:G transversions of the p53 gene are observed at a higher frequency (56 of 1176; 4.8%) in human breast cancers than in overall human cancers (375 of 9959; 3.8%; Ref. 18 ),5 and some of this increase could be explained by the hypothesis that SNI with a high frequency of A:T to C:G transversions is one of the early events in human breast carcinogenesis. As molecular abnormalities that induce a high frequency of A:T to C:G transversions, mutations of MutT in Escherichia coli (19) and replication using DNA polymerase {kappa} in mammalian cells (20 , 21) have been reported. Analysis on inactivation of MTH1 and overexpression of polymerase {kappa} will be of interest.

An appropriate marker gene that could be analyzed also in primary carcinomas was not available in this study, and the presence of SNI in human primary breast cancers still needs confirmation. However, in our previous study using lacI-transgenic rats, the marker transgene served to demonstrate that the increase of A:T to C:G transversions was present not only in the cell lines but also in the primary carcinomas. Therefore, we would expect that a common molecular alteration(s) would be present again in human breast cancer cell lines and primary cancers.


   ACKNOWLEDGMENTS
 
We thank Dr. S. M. Nagao and T. Ishikawa for their critical discussion.


   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 Supported by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare of Japan. E. O. is a recipient of a Travel Fellowship from the Sankyo Foundation. Back

2 To whom requests for reprints should be addressed, at Carcinogenesis Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan. Fax: 81-3-5565-1753; E-mail: tushijim{at}ncc.go.jp Back

3 The abbreviations used are: MSI, microsatellite instability; HMEC, human mammary epithelial cell; hprt, hypoxanthine-guanine phosphoribosyltransferase; MR, mutation rate; SNI, single nucleotide instability; 6TG, 6-thioguanine; MF, mutant frequency. Back

4 Internet address: http://www.ncc.go.jp/research/rat-genome/. Back

5 Internet address: http://perso.curie.fr/Thierry.Soussi/p53_databaseWh.htm. Back

Received 7/20/01. Accepted 9/14/01.


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 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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