乳腺癌的分子生物学进展（二）

1、Figure: Amplification of the EGFR gene in human breast carcinoma. The EGFR gene, becomes amplified and is seen either as extra chromosomal double minutes or as a chromosomally integrated, homogeneously staining region. Adapted from Robbins Basic PathologyEGFREGFRInsensitivity to growth-inhibitory signals: tumor suppressor genes The proteins that apply brakes to cell proliferation are the products of tumor suppressor genes, which can be inactivated by epigenetic (表观遗传学，gene hypermethylation) and

2、genetic alterations (gene mutation/deletion). lTP53: mutationlP16: gene hypermethylation or mutation or mutationlPTEN: mutation mutation Figure: genetic gene silencingFigure: the dynamics of epigenetic gene silencing Figure: epigenetic silencingEpigenetics affects genes expressionEpigenetics affects genes expressionl ltumor suppressor genes, such astumor suppressor genes, such as p16 (INK4a)p16 (INK4a), , p15 p15 (INK4b)(INK4b), , p14 (ARF) p14 (ARF) and and adenomatousadenomatous polyposis coli

3、 polyposis coli (APC)(APC)l lDNA repair genes, such as human DNA repair genes, such as human Mut L homologue Mut L homologue 1 1 (hMLH1)(hMLH1), , glutathione S-transferase P1 glutathione S-transferase P1 ( (GSTP1， 谷胱甘肽S-转移酶P1 ) and and O6-methylguanine-DNA O6-methylguanine-DNA methytransferase methytransferase (MGMT)(MGMT)l lgenes related to metastasis and invasion, such as genes related to metastasis and invasion, such as E-E- cadherin cadherin (CDH1),(CDH1), tissue inhibitor of tissue inhibit

4、or of metalloproteinase-3 metalloproteinase-3 (TIMP3)(TIMP3) and and death associated death associated protein kinase (DAPK)protein kinase (DAPK) Epigenetics affects genes mutationEpigenetics affects genes mutationl lCytosine methylation in the coding region of genes can increase Cytosine methylation in the coding region of genes can increase mutation rates because of the spontaneous hydrolytic mutation rates because of the spontaneous hydrolytic deamination of methylated cytosine, which causes

5、C to T deamination of methylated cytosine, which causes C to T transition mutations at methylated CpG sites. transition mutations at methylated CpG sites. l lMethylation also changes the absorption wavelength of cytosine, Methylation also changes the absorption wavelength of cytosine, into the range of incident sunlight, resulting in CC to TT into the range of incident sunlight, resulting in CC to TT mutations, which commonly occur in skin cancers. mutations, which commonly occur in skin cancers

6、. l lMethylated CpGs are also preferred binding sites for Methylated CpGs are also preferred binding sites for benzo(a)pyrene diolepoxide (benzo(a)pyrene diolepoxide (环氧化物苯并芘环氧化物苯并芘) and other ) and other carcinogens that are found in tobacco smoke. These cause DNA carcinogens that are found in tobacco smoke. These cause DNA adducts and G to T transversion mutations, which are often adducts and G to T transversion mutations, which are often found in the aerodigestive tumours of smokers. found in

7、 the aerodigestive tumours of smokers. Figure: The role of p53 in maintaining the integrity of the genome. The role of p16, which is inactivated by gene mutation or promoter hypermethylation PI3K:PI3K:磷脂酰肌醇磷脂酰肌醇-3-3-激酶激酶 PIP2:PIP2:磷酯酰肌醇磷酯酰肌醇-4,5-4,5-二磷酸二磷酸 PIP3:PIP3:磷酯酰肌醇磷酯酰肌醇-3,4,5-3,4,5-三磷酸三磷酸Defects in DNA repairlDNA damage from environmental agentslDNA alterations resulting from errors that occur spontaneously during DNA replicationDefects in three types of DNA repair systems:l mismatch repa

8、irGerm line mutations in the MSH2 (2p16) and MLH1 (3p21) genes each account for approximately 30% of Hereditary Nonpolyposis Cancer Syndrome.l nucleotide excision repairXeroderma Pigmentosumlrecombination repairGerm line mutation of Brcca1 and Brca2 in breast cancermismatch repairExcision repairExcision repairExcision repairExcision repairrecombination repairInteracting proteins of Brca1 and Brca2Interacting proteins of Brca1 and Brca2绿色：基因灭活表现为基因突变绿色：基因灭活表现为基因突变 红色：基因灭活表现为基因甲基化红色：基因灭活表现为基因甲基化 紫

9、色：基因灭活表现为基因突变和甲基化紫色：基因灭活表现为基因突变和甲基化The molecular basis of cancerEvasion of apoptosisAccumulation of neoplastic cells may occur not only by the activation of oncogenes or inactivation of tumor suppressor genes, but also by mutations in the genes that regulate apoptosis. Figure: The extrinsic (death receptor-initiated) pathway of apoptosis, illustrated by the events following Fas engagement. Figure: The intrinsic (mitochondrial) pathway of apoptosis. Death agonists cause changes in the inner mitochondrial membrane, resulting in the mitochondrial permeability transition (MPT) and release of cytochrome c and other pro-apoptotic proteins into the cytosol, which activate caspases. Limitless replicative potential: telomerase (端粒酶) Telomerase activity and maintenance of telomere length are essential for the maintenance of replicative potential in cancer cells.The molecular basis of cancerThe telomere-telomerase hypothesis - chang

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