乳腺癌的分子生物学进展

1、EpidemiologyBreast carcinomasCancer and cardiovascular diseases are the leading causes of death around the world.Cancers arising in tissues such as stomach, 1 lung, breast, nasopharynx and bone marrow ar very common in China.(Adapted from Jemal A, et al: Cancer statistics, 2003. CA Cancer J Clin 53:

2、5, 2003.WHO 2007 Worldwide, the most common malignant tumors in males are cancers of lung, stomach, liver, colon/rectum and esophagus. Worldwide, the most common malignant tumors in females are cancers of breast, lung, stomach, colon/rectum and cervix.2007 CSCO Annual Meeting（2007年全国临床肿瘤学大会） In Chin

3、a, the most common malignant tumors in males are cancers of lung, stomach, liver, colon/rectum and esophagus. In China, the most common malignant tumors in females are cancers of breast, lung, colon/rectum stomach and liver.Breast carcinomaBreast carcinoma is the most common malignancy in women. A w

4、oman who lives to age 90 has a one in eight chance of developing breast cancer.50966T686LIn Situ Stage I Stage II Stage lll-IVPart 1EpidemiologyStudy of cancer patterns in populations, cancer epidemiology, can contribute substantially to knowledge about the origins of cancer.Breast cancer risk facto

5、rs Well-confirmed factors Probable factorsFactor 1: Geographic location low-risk: Far East, Africa and South America high-risk: North America and Northern Europe areas.EpidemiologyFactor 2: Age Breast cancer is rarely found before the age of 25 years except in certain familial cases. The incidence r

6、ises throughout a woman's lifetime Seventy-seven per cent of cases occur in women ov( 50 years of age. The average age at diagnosis is 64 years.Factor 3: Early Age of Menarche Women who reach menarche when younger than 1 years of age have a 20% increased risk compared t women who reach menarche

7、when more than 14 years of age. It is probably because of a prolonged exposure of breast epithelium to estrogens and progesterone di to earlier regular ovulatory menstrual cycles.Factor 4: Late Age of Menopause Late menopause (>54) also increases risk, but the magnitude of the risk has not been q

8、uantified. In contrast, surgically-induced menopause (ovariectomy or hysterectomy) before the age of 35 results in a decrease of breast cancer risk. Evei unilateral ovariectomy performed before the age of 45 has been demonstrated to be protective.Factor 5: Nulliparity and older age at first live bir

9、th Women with a first full-term pregnancy at younger th ar 20 years of age have half the risk of nulliparous women or women over the age of 35 at their first birth. Interestingly, women with their first birth after age of 3： are even at higher risk than nulliparous women. One mechanism may involve a

10、 markedly reduced susceptibility of the fully mammary gland to carcinogens, due to in part a decrease in proliferati activity of parous (经产的)epithelium. Another possibility is due to the altered hormonal environment during pregnancy (e.g. decrease in circulating growth factor hormone etc).Factor 6:

11、Family history of breast cancerWomen with one, two, and three or more first- degree affected relatives have an increased breast cancer risk when compared with women who do nc have an affected relative (risk ratios 1.8, 2.9 and 3. respectively) Breast cancer occurring before age 50 (premenopausal) in

12、 first- or second-degree relative(s) Two or more first- or second-degree relatives with breast or ovarian cancer One or more first-, second-, or third-degree relative(s) with breast anc ovarian cancer or with two separate or independent breast cancers Male relative(s) with breast cancer One or more

13、first-, second-, or third-degree relative(s) with BRCA1 and/or BRCA2 gene mutationNote. First-degree relatives are mother, daughter, sister, father, son, and brother. Second-degree relatives are grandmother, aunt, niece, grandfather, uncle, and nephew. Third-degree relatives are greatgrandmother, gr

14、eat-grandfather, great-aunt, great-uncle, and female e male first cousins.Figure 1. Family History That Increases Breast Cancer RiskHereditary Breast Cancer About 25% of familial breast cancers (or around 3% of all breast cancers) can be attributed to tw highly penetrant autosomal dominant genes: BR

15、CA1 and BRCA2. About 10% of familial breast cancers are attributed to p53, PTEN, CHEK2, ATM genes.Factor 7: Intake of Exogenous hormones Postmenopausal hormone replacement therapy increase the risk of breast cancer depending on the duration of exposure and whether the estrogen is used alone or in co

16、mbination with progestin. When taking oral contraceptive, women with a family history have a significant increase in breast cancer riskHormone acts as a promoterKnudson proposed that carcinogenesis requires two phases.The first event is initiation and the carcinogen causing it is the initiator9The s

17、econd event, which induces neoplastic growth, i promotion （促进），and the agent is the promoter.APPLICATION ot test chemicals to mouse skininitiatorPolycyclic hydrocarbons alone (high dose)» LAG DEVELOPMENTTIMEOF CANCERPolycyclic hydrocarbons alone (low dose)Figure: Initiation and promotion of a n

18、eoplasm. Polycyclic hydrocarbons (多环炸，which arc carcinogens doses, cause skin cancer. The action of polycyclic hydrocarbons is enhanced by croton oil (匕豆油).which a promoter. This is best seen by the effect of croton oil in producing cancer when a subcarcinogenic (low) polycyclic hydrocarbon is used.

19、 Note that croton oil in any dose does not cause cancer. Many carcinogens both initiators and promotersAdapted from Kumar: Robbins and Cotran: Pathologic Basis Carcinogenic agentsInitiation and promotionInitiation causes permanent DNA damage (mutations). It rapid and irreversible and has nmemory.H A

20、n initiated cell ii potentially capable of giving rise to a tumor. Initiation alone however, is not sufficient for tumor formation.Promoters can induce tumors in initiated cells, but they ai nontumorigenic by themselves. The cellular changes resultii from the application of promoters do not affect D

21、NA directl and are reversible.High breast density and nulliparity seem to act synergistically since the breast cancer risk goes up sevenfold when they are both present in a person.Factor 9: Alcohol consumption There is a positive association between alcohol intake and the risk of developing breast c

22、ancer ir both pre- and postmenopausal women. Alcohol can act indirectly through its first metabolite, acetaldehyde （乙醛）,a carcinogen and mutagen, and/or can be a tumor promoter, leading to enhanced procarcinogen activation.Factor 10: Obesity in postmenopausal women For each 5 kg of weight gain since

23、 the lowest weight, breast cancer risk increases by 8%. It may be through higher levels of endogenous estrogen in obese women, as adipose tissue is an important source of estrogens.Breast cancer probable factors High insulin-like growth factor I levels High prolactin （催乳素）levels High saturated fat a

24、nd well-done meat intake High socioeconomic statusFactors that decrease breast cancer risk Geographic region (Asia and Africa) Early age of first full-term pregnancy Higher parity Breast feeding (longer duration) Obesity in premenopausal women Fruit and vegetable consumption Physical activity Chemop

25、reventive agents: tamoxifen, an antagonist of tl estrogen receptor in breast tissueMolecular epidemiology a science that focuses on the contribution of potential genetic and environmental risk factors, identified at the molecular level, to the etiology, distribution and prevention of disease within

26、families and across populations.CG 。） C Q 0 S 0 3InversionInsertionC 0 6 3 C5GCJcMc：DeletionCopy number variationCOOReferenceWhat makes us unique. Changes in the number and orde of genes （A-D） add variety to the human genome.High-penetrant （夕卜显性）breast cancer susceptibility ge Brcal Brca2 P53 PTEN A

27、TM Presence of BRCA1 and/or BRCA2 gene mutation or strong family history and younger than age 25- - Clinical breast examination (CBE) every 6-12 months/ - Self-awareness of changes in the breasts, with monthly selfbreast examination (SBE) encouraged* Presence of BRCA1 and/or BRCA2 gene mutation or s

28、trong family history, beginning at age 25-/ - CBE every 6-12 months- - Self-awareness of changes in the breasts with monthly SBE encouragedJ - Annual mammographyJ - Annual magnetic resonance imagingFigure 2. 2007 Breast Cancer Screening Guidelines for Women at High RiskLow-penetrant breast cancer su

29、sceptibility genesPolymorphisms in breast cancer susceptibility genes with low-penetrance (but present in a high percentage of individuals) have a greater contribution to breast tumorigenesis in combination with exogenous (e.g. diet, pollution and endogenous (e.g. hormones) exposures.Polymorphism of

30、 p2 -adrenergic receptor geneAt nucleotide position 46, there can be a adenine (A) or a guanine (G) that results 16th amino acid in the receptor being ar or glycine, respectively. The site of the resulting amino acid in the extracellular of the receptor is indicated. Similarly, nucleotide substituti

31、ons of C to G, G to . C to T at nucleotide positions 79. 100, a result in substitutions of glutamine to gl valine to methionine, and threonine to isoleucine at amino acid positions 27, 3/ 164, respectively. Although these examp for coding nonsynonymous SNPs that cl the amino acid sequence, the vast

32、major SNPs occur in non-amino acid coding re of DNA where they have cither no effee influence transcription factor binding sit messenger RNA splicing or stability.Candidate polymorphic genes enzymes implicated in the metabolism of estroge or various carcinogens, detoxification of reactive oxygen spe

33、cies (活，性 氧)emerging from these reactions, alcohol and one-carbon metabolism pathways proteins that play a role in DNA repair or cellsignaling processesPart 2Carcinogenesis: The molecular basis of cancerNonlethal genetic damage lies at the heart of carcinogenesis.Tumor is monoclonal (单克隆性)Four class

34、es of normal regulatory genes are the principal tar* of genetic damage>the growth-promoting protooncogenes (原癌基因).>the growth-inhibiting tumor suppressor genes (月中瘤 才卬帘J>genes that regulate programmed cell death (apoptosis)>DNA repair genesCarcinogenesis is a multistep process at both th

35、e phenotypic the genetic levels.Adapted from Robbins Basic PathoUBlastocystinactivation of one X chromosomeNeoplasmsFemale zygoteI Monoclonal neoplasm (one isoenzyme)Polyclonal neoplasm <two isoenzymes)Figure: Diagram depicting the use of X-linked isoenzyme cell markers as evidence of the monoclo

36、nality of neoplasms. Because of random X inactivation, all females are mosaics with two cell populations (with G6PD isoenzyme A or B in this case). When neoplasms that arise in women who are heterozygous for X-linked markers are analyzed, they are made up of cells that contain the active maternal (XA ) or the paternal (XB ) X chromosome but not both.Demonstration of X-InactivationG6PD: glucose-6-phosphate dehydrogenase enzyme PGK: phosphoglycerol kinase enzymeEssential alterations for malignant transformationSelf-suffi