Structural and functional analysis of β2 microglobulin abnormalities in human lung and breast cancer

Chen, Hailei L.; Gabrilovich, Dmitry I.; Virmani, Arvind K.; Ratnani, Ikki; Girgis, Khaled R.; Nadaf-Rahrov, Sorena; Fernández-Viña, Marcelo; Carbone, David P.

doi:10.1002/(sici)1097-0215(19960917)67:6<756::aid-ijc2>3.0.co;2-q

Cited by 58 publications

(18 citation statements)

References 27 publications

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“…However, Chen et al. (39), also using SSCP analysis, failed to find any mutations in 70 fresh human tumor samples (including 63 breast cancers) and found only two mutations (in one lung adenocarcinoma and one colon cancer) in a further 40 human tumor cell lines. Feenstra et al.…”

Section: Discussionmentioning

confidence: 99%

Frequency and genetic basis of MHC, beta‐2‐microglobulin and MEMO‐1 loss of heterozygosity in sporadic breast cancer

et al. 2002

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The Human Leukocyte Antigen (HLA) class I molecules are critical factors in T cell recognition of abnormal, including neoplastic, cells. Loss of HLA class I expression phenotypes, as defined by immunohistochemistry-based tests, have been previously described in many types of cancer. Here we describe a microsatellite marker DNA-based loss of heterozygosity (LOH) analysis of three distinct chromosomal regions which have been implicated in HLA class I expression on a cohort of 99 unselected sporadic breast cancer samples. These regions comprise the 4Mb major histocompatibility complex (MHC) region on chromosome 6p, which contains the HLA class I heavy chain loci and other genes responsible for antigen processing, the HLA class I light chain (beta-2-microglobulin, beta2m) gene on chromosome 15q, and the putative HLA class I modifier of methylation gene (MEMO-1) on chromosome 1p. Additional chromosome 6 markers were also employed to determine the likely genetic mechanism for MHC loss. We show that 25/99 (25%) of samples show allelic loss within the MHC, 28/95 informative samples (29%) show allelic loss of beta2m and 21/76 informative samples (28%) show allelic loss of MEMO-1. Approximately half of the samples are predicted to have compromised HLA class I gene expression due to LOH at one and/or other of these three loci. Sequencing of the remaining beta2m allele in samples displaying beta2m LOH failed to detect any additional intragenic mutations. Analysis of the frequency of samples showing LOH at either 0, 1, 2 or 3 of the genomic regions analyzed suggested clustering of tumors into either 'no loci loss' or '3 loci loss' categories. These results reveal major underlying genetic causes for the high level of HLA class I expression loss seen in breast cancer.

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Section: Discussionmentioning

confidence: 99%

Frequency and genetic basis of MHC, beta‐2‐microglobulin and MEMO‐1 loss of heterozygosity in sporadic breast cancer

et al. 2002

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“…Phenotype I, HLA class I total loss, can be associated with a lack of synthesis or synthesis of a truncated β2‐m. There are indications that β2‐m mutations are involved in some cases of HLA class I total loss observed in colorectal carcinomas (Browning et al, 1996), melanomas (Benitez et al, 1998; Wang et al, 1999), lung adenocarcinomas (Chen et al, 1996), and Burkitt's lymphoma (Rosa et al, 1983). A summary of such mutations was recently published (Garrido and Algarra, 2001).…”

Section: Molecular Mechanisms Leading To Mhc Class I Lossesmentioning

confidence: 99%

MHC class I antigens, immune surveillance, and tumor immune escape

García-Lora

Algarra

Garrido

2003

Journal Cellular Physiology

431

308

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Oncogenic transformation in human and experimental animals is not necessarily followed by the appearance of a tumor mass. The immune system of the host can recognize tumor antigens by the presentation of small antigenic peptides to the receptor of cytotoxic T-lymphocytes (CTLs) and reject the nascent tumor. However, cancer cells can sometimes escape these specific T-cell immune responses in the course of somatic (genetic and phenotypic) clonal evolution. Among the tumor immune escape mechanisms described to date, the alterations in the expression of major histocompatibility complex (MHC) molecules play a crucial step in tumor development due to the role of MHC antigens in antigen presentation to T-lymphocytes and the regulation of natural killer cell (NK) cell function. In this work, we have (1) updated information on the mechanisms that allow CTLs to recognize tumor antigens after antigen processing by transformed cells, (2) described the altered MHC class I phenotypes that are commonly found in human tumors, (3) summarized the molecular mechanisms responsible for MHC class I alteration in human tumors, (4) provided evidence that these altered human leukocyte antigens (HLA) class I phenotypes are detectable as result of a T-cell immunoselection of HLA class I-deficient variants by an immunecompetent host, and (5) presented data indicating the MHC class I phenotype and the immunogenicity of experimental metastatic tumors change drastically when tumors develop in immunodeficient mice.

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“…Several studies have described down-regulation of MHC class I in a number of tumor specimens, including melanoma, breast, cervical and colorectal cancers, small cell lung cancer (SCLC) cell lines, Burkitt's lymphoma, prostate carcinoma and renal cell carcinoma cell lines (Restifo et al, 1993;Kaklamanis et al, 1995;Chen et al, 1996;Vitale et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

β2-microglobulin induces apoptosis in HL-60 human leukemia cell line and its multidrug resistant variants overexpressing MRP1 but lacking Bax or overexpressing P-glycoprotein

Rastegar

Gordon

et al. 2001

Oncogene

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In this study, we examined whether exogenous b 2 -microglobulin (b 2 m) can induce apoptosis in the drug sensitive HL-60 leukemia cell line and its drug resistant variants and investigated the molecular mechanism of b 2 m-induced apoptosis. Our data revealed that b 2 m is very signi®cantly down-regulated in two multidrug resistant variants of the HL-60 cells: (a) the MRP1-bearing, Bax-de®cient HL-60/ADR cell line, and (b) the P-glycoprotein (P-gp) overexpressing HL-60/VCR cell line. However, exogenous b 2 m induced similar levels of apoptosis in HL-60 cells and these drug resistant variants. b 2 m-induced apoptosis in HL-60 and HL-60/ VCR cells was associated with decreased mitochondrial membrane potential (Dcm) but did not a ect Dcm in HL-60/ADR cells. Surprisingly, cyclosporin A (CsA), a known inhibitor of the mitochondrial permeability transition (MPT) pore, inhibited b 2 m-induced apoptosis in HL-60/ADR cells but not in HL-60 and HL-60/VCR cells, suggesting that the pro-apoptotic e ect of b 2 m in these cells is not through MPT pore formation. Furthermore, b 2 m induced the release of cytochrome c and the apoptosis-inducing factor (AIF) from mitochondria in HL-60 and HL-60/VCR cells, but not in HL-60/ ADR cells. Additionally, Z-VAD-fmk, a general inhibitor of caspases which inhibited cytochrome c release in HL-60 and HL-60/VCR cells, had no e ect on AIF release in any of these cell lines, but inhibited b 2 m-induced apoptosis in all three cell lines. However, Western blot analysis revealed that caspases-1, -3, -6, -8, and -9 are not activated during b 2 m-induced apoptosis in these cells. Therefore, b 2 m-induces apoptosis through an unknown caspase-dependent mitochondrial pathway in HL-60 and HL-60/VCR cells and by a Bax-independent, nonmitochodrial, caspase-dependent pathway in HL-60/ ADR cells. Oncogene (2001) 20, 7006 ± 7020.

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Structural and functional analysis of β2 microglobulin abnormalities in human lung and breast cancer

Cited by 58 publications

References 27 publications

Frequency and genetic basis of MHC, beta‐2‐microglobulin and MEMO‐1 loss of heterozygosity in sporadic breast cancer

Frequency and genetic basis of MHC, beta‐2‐microglobulin and MEMO‐1 loss of heterozygosity in sporadic breast cancer

MHC class I antigens, immune surveillance, and tumor immune escape

β2-microglobulin induces apoptosis in HL-60 human leukemia cell line and its multidrug resistant variants overexpressing MRP1 but lacking Bax or overexpressing P-glycoprotein

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