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The Tumor Suppressor Gene LKB1 Is Associated with Prognosis in Human Breast Carcinoma1

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The Tumor Suppressor Gene LKB1 Is Associated with Prognosis in Human Breast Carcinoma1 Vol. 8, 2085–2090, July 2002 Clinical Cancer Research 2085 Advances in Brief The Tumor Suppressor Gene LKB1 Is Associated with Prognosis in Human Breast Carcinoma1 Zan Shen, Xian-Feng Wen, Fei Lan, patients with PJS (1). PJS is an autosomal dominant-inherited Zhen-Zhou Shen, and Zhi-Ming Shao2 disorder, which is characterized by predisposition to gastroin- testinal polyposis, mucocutaneous melanin pigmentation, and Department of Surgery, Cancer Hospital/Cancer Institute, Fudan University, Shanghai 200032, People’s Republic of China [Z. S., various neoplasms (1). The incidence of cancer among patients X-F. W., F. L., Z-Z. S., Z-M. S.] with PJS has been estimated to be 18-fold higher than in the general population (1). Moreover, tumors associated with PJS have acquired somatic mutations in the remaining wild-type Abstract allele of LKB1, strongly implicating LKB1 as a tumor suscep- Purpose: LKB1 (also called STK11) is a recently iden- tibility gene (2). Most of the mutations in PJS families are point tified tumor suppressor gene in which its mutation can lead and truncation mutations within the kinase domain of LKB1, to Peutz-Jeghers syndrome, characterized by gastrointesti- suggesting that the kinase activity of LKB1 is critical to its nal polyps and cancers of different organ systems. Weak function (1, 3). expression of this gene does occur at a certain frequency in Because PJS patients show a predisposition to a wide sporadic breast cancer. This indicates that LKB1 gene may spectrum of cancers, including breast cancer, it is speculated relate to the tumorigenesis of breast cancer. that LKB1 has a tumor suppressor function in the breast cancer Experimental Design: To investigate the function of the of PJS. A report of 31 sporadic breast cancers showed weak LKB1 gene in sporadic breast cancer, we reintroduced LKB1 LKB1 expression in 9 cases of cancer (4). We ask that if the into breast cancer cell lines which lack the LKB1 gene. Also, LKB1 gene has a role in breast cancer malignant formation, what we examined the LKB1 protein expression in human breast is the mechanism of this tumor suppressor function? To inves- cancer samples. tigate the function and the mechanism of LKB1 in sporadic Results: We found that reintroducing LKB1 into breast breast cancer, we have identified breast cancer cell lines with cancer cell lines suppresses cell growth by G1 cell cycle severely reduced LKB1 mRNA and protein expression and block. The LKB1-mediated G1 cell cycle arrest is caused by transfected the LKB1 gene into one of these, the MDA-MB-435 WAF1/CIP1 up-regulation of the expression of p21 in breast cells. We found that the LKB1 overexpression can result in G1 cancer MDA-MB-435 cells. We also demonstrated that low cell cycle arrest, which is accompanied by p21WAF1/CIP1 induc- LKB1 protein expression correlates with higher histological tion. We also investigated LKB1 protein expression in 116 cases progester- of human breast cancer samples and demonstrated that low ,(0.001 ؍ larger tumor size (P ,(0.013 ؍ grade (P and presence of lymph node LKB1 protein expression correlated with higher histological ,(0.048 ؍ one receptor status (P Furthermore, LKB1 low expression grade, larger tumor size, presence of lymph node metastasis, and .(0.003 ؍ metastasis (P .and a shorter survival (0.002 ؍ was associated with a higher relapse rate (P .(0.008 ؍ worse OS (P Conclusions: LKB1 plays a role in tumor suppressor Materials and Methods function in human breast cancer. LKB1 expression may be a useful prognostic marker in human breast cancer. Construction of the LKB1 Expression Plasmid. The expression plasmid pcDNA3.1/LKB1 myc, which contains the wild-type LKB1 coding sequence, was constructed by PCR. A Introduction DNA fragment amplified by PCR, by use of an LKE1 primer The LKB1/STK11 gene (locus on 19p13.3) encodes a (5Ј-GATGAATTCGGGTCCAGCATGGAGGTGGTGGAC- serine/threonine protein kinase and is deficient in the majority of 3Ј) and an LKE2 primer (5ЈGATGAATTCTTAGAGGTCT- TCTTCTGAGATGAGCTTCTGCTCCTGCTGCTTGCAGGC- CGA-3Ј), was cloned into an EcoRI site of the pcDNA3 vector. The clones with the correct orientation were selected, and their Received 11/12/01; revised 4/15/02; accepted 4/26/02. The costs of publication of this article were defrayed in part by the sequences were verified. payment of page charges. This article must therefore be hereby marked Cell Culture and Transfections. ER-positive breast advertisement in accordance with 18 U.S.C. Section 1734 solely to cancer cell line MCF-7 and ER-negative breast cancer cell lines indicate this fact. MDA-MB-435 and MDA-MB-231 were grown in MEM sup- 1 Supported in part by the Outstanding Young Investigator Award of plemented with 10% (v/v) fetal bovine serum and antibiotics National Natural Science Foundation of China (30025015) and National ␮ Key Project of China (2001BA703BO5). (100 units/ml penicillin and 100 g/ml streptomycin). These 2 To whom requests for reprints should be addressed, at Department of cells were cultured as monolayers in a 95% air, 5% CO2 Breast Surgery, Cancer Hospital/Cancer Institute, Fudan University, 399 water-saturated atmosphere. RT-PCR and Western blot have Ling-Ling Road, Shanghai, 200032, People’s Republic of China. Fax: shown MDA-MB-435 cells that lack the LKB1 gene (Fig. 1 in 86-21-64174774; E-mail: [email protected]. 3 The abbreviations used are: PJS, Peutz-Jeghers syndrome; ER, estro- “Results”). Then, MDA-MB-435 cells were transfected with gen receptor; RT-PCR, reverse transcription-PCR; RFS, relapse-free pcDNA3.1/LBK1 expression vector with the lipofectAMINE survival; OS, overall survival; CdK, cyclin-dependent kinase. method (Life Technologies, Inc., Rockville, MD). The trans- Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2002 American Association for Cancer Research. 2086 LKB1 as a Tumor Suppressor in Human Breast Cancer fected cells were subjected to 1 mg/ml G418 (Life Technolo- Table 1 Patient demographics gies, Inc.) selection. No. of Patients Isolation of RNA and RT-PCR. Total RNA was ex- (N ϭ 116) tracted with Trizol (Life Technologies, Inc.). An amount of 0.8 Age (yrs.) ␮g of RNA was used in the reverse transcription reaction. The Median 53.7 standard random priming method with Moloney murine leuke- Range 32–77 mia virus reverse transcripts (Promega) and RNase inhibitor Ͻ50 years 43 Ն (Promega, Madison, WI) was used to obtain 20 ␮l of cDNA. 50 years 78 Surgical treatment The following primers were used to amplify most of the coding Lumpectormy 7 region of LKB1: LKBF1, 5Ј-GAGCTGATGTCGGTGGGTAT- Lumpectormy ϩ radiotherapy 40 3Ј; and LKBR5, 5Ј-GCCCTGGATTTGGTGCTC-3Ј. PCR was Mastectormy 74 ␮ ␮ ϫ Tumor size (cm) carried out in a volume of 50 l containing 3 l of cDNA, 1 Ͻ ␮ 3cm 51 PCR buffer (Promega), 2.5 mM MgCl2, 200 M of each de- Ն3cm 70 oxynucleotide triphosphate (Promega), each primer at 0.8 ␮M, Node status 10% DMSO, and 2 units of polymerase (Promega). Cycling Negative 46 conditions were performed as described previously (5). Positive 75 Western Blotting. Cells were washed twice with ice- Histological type Ductal 96 cold PBS and scarped into 1 ml of ice-cold NP40 lysis buffer Lobular 8 [10 mM Tris-HCl (pH 8.0), 150 mM NaCl, 1% (v/v) NP40, 1 mM Medullary 7 Paget’s disease 1 EDTA, 50 mM NaF, 5 mM Na PPI,1mM phenylmethylsulfonyl fluoride, 1 ␮g/ml leupeptin, and 1 ␮g/ml pepstatin A]. Cells Adenocarcinoma 5 Others 4 were then sonicated for5sat5W.Insoluble debris was Grade removed by centrifugation at 1000 ϫ g for 15 min. Total 117 proteins (200 ␮g) were analyzed by 10% SDS-PAGE. Western 257 blot, using murine monoclonal antibodies to p21WAF1/CIP1 (On- 347 cogene Research Products, Cambridge, MA), cyclin D1 and ER status Positive 78 cyclin E (Santa Cruz Biotech, San Diego, CA), and LKB1 Negative 43 polyclonal antibody (Upstate Biotechnology, Lake Placid, NY), PR status was performed according to standard protocols (6, 7). Blot Positive 70 quantitation was done with a Molecular Dynamics Laser Negative 51 Adjuvant therapy Densitometer (Model PSD) and the Image Quant Version 1 Chemotherapy 56 software. Hormonal therapy (tamoxifen) 43 Analysis of Cell Cycle Phase Distribution. Flow cy- Duration follow-up (mo) tometry analysis of DNA content was performed to assess the Median 44.5 cell cycle phase distribution as described previously (6). Cells Range 10–70 Relapses 26 were harvested and stained for DNA content using propidium Deaths 15 iodide fluorescence. The computer program Multicycle from Phenix Flow System (San Diego, CA) was used to generate histograms, which were used to determine the cell cycle phase distribution. Patient Follow-up. All patients were followed up after Human Breast Cancer Samples Collection and Protein surgical treatment. Physical examination was performed every 3 Preparation. A total of 116 patients with histologically con- months in all patients for the first 2 years and then twice/year. firmed local breast carcinoma was included in this study. This Mammography, radiographic studies (chest X-ray), and liver study was performed at the Cancer Hospital of the Shanghai ultrasounds were performed every 12 months; bone scans and Medical University between March 1995 and December 2000. computed tomography scans were performed whenever clini- All of the patients were from the Cancer Hospital of the Shang- cally indicated. Blood tests, including electrolyte and liver func- hai Medical University. The mean age is 53.7 years old, and the tion profiles and complete blood cell counts, were repeated at clinical data are shown in Table 1. The protocol of this study every follow-up visit. RFS was calculated as the period from was approved by the human research committees of the Cancer surgery until the date of the first recurrence.
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