乳腺癌的分子生物学进展（一）.ppt

1、Breast carcinomas,Cancer and cardiovascular diseases are the leading causes of death around the world. Cancers arising in tissues such as stomach, liver, lung, breast, nasopharynx and bone marrow are very common in China.,(Adapted from Jemal A, et al: Cancer statistics, 2003. CA Cancer J Clin 53:5,

2、2003.),Epidemiology,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.,WHO 2007,2007 CSCO Annual Meeting(2007年全国临床肿

3、瘤学大会),In China, 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 carcinoma,Breast carcinoma is the most common malignan

4、cy in women. A woman who lives to age 90 has a one in eight chance of developing breast cancer.,Epidemiology Study of cancer patterns in populations, cancer epidemiology, can contribute substantially to knowledge about the origins of cancer.,Part 1,Breast cancer risk factors Well-confirmed factors P

5、robable factors,Factor 1: Geographic location,low-risk: Far East, Africa and South America high-risk: North America and Northern Europe areas.,Epidemiology,Factor 2: Age Breast cancer is rarely found before the age of 25 years except in certain familial cases. The incidence rises throughout a womans

6、 lifetime. Seventy-seven per cent of cases occur in women over 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 12 years of age have a 20% increased risk compared to women who reach menarche when more than 14 years

7、of age. It is probably because of a prolonged exposure of breast epithelium to estrogens and progesterone due 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 quantified. In contrast, su

8、rgically-induced menopause (ovariectomy or hysterectomy) before the age of 35 results in a decrease of breast cancer risk. Even unilateral ovariectomy performed before the age of 45 has been demonstrated to be protective.,Factor 5: Nulliparity and older age at first live birth Women with a first ful

9、l-term pregnancy at younger than 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 35 are even at higher risk than nulliparous women.,One mechanism may involve a markedly reduced suscepti

10、bility of the fully mammary gland to carcinogens, due to in part a decrease in proliferative 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: Family history of brea

11、st cancer Women with one, two, and three or more first-degree affected relatives have an increased breast cancer risk when compared with women who do not have an affected relative (risk ratios 1.8, 2.9 and 3.9, respectively),Hereditary Breast Cancer,About 25% of familial breast cancers (or around 3%

12、 of all breast cancers) can be attributed to two highly penetrant autosomal dominant genes: BRCA1 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 increases the risk of bre

13、ast cancer depending on the duration of exposure and whether the estrogen is used alone or in combination with progestin. When taking oral contraceptive, women with a family history have a significant increase in breast cancer risk.,Hormone acts as a promoter,Knudson proposed that carcinogenesis req

14、uires two phases. The first event is initiation (激发), and the carcinogen causing it is the initiator. The second event, which induces neoplastic growth, is promotion (促进), and the agent is the promoter.,Adapted from Kumar: Robbins and Cotran: Pathologic Basis of Disease,Figure: Initiation and promot

15、ion of a neoplasm. Polycyclic hydrocarbons (多环烃), which are carcinogens at high doses, cause skin cancer. The action of polycyclic hydrocarbons is enhanced by croton oil (巴豆油), which acts as a promoter. This is best seen by the effect of croton oil in producing cancer when a subcarcinogenic (low) do

16、se of polycyclic hydrocarbon is used. Note that croton oil in any dose does not cause cancer. Many carcinogens act as both initiators and promoters,Carcinogenic agents,Initiation and promotion Initiation causes permanent DNA damage (mutations). It is rapid and irreversible and has memory. An initiat

17、ed cell is 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 are nontumorigenic by themselves. The cellular changes resulting from the application of promoters do not affect DNA di

18、rectly and are reversible.,Factor 8: High mammographic breast density,High breast density and nulliparity seem to act synergistically since the breast cancer risk goes up to sevenfold when they are both present in a person.,Factor 9: Alcohol consumption,There is a positive association between alcoho

19、l intake and the risk of developing breast cancer in 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 postmenop

20、ausal women For each 5 kg of weight gain since 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

21、High prolactin （催乳素）levels High saturated fat and well-done meat intake High socioeconomic status,Factors 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 an

22、d vegetable consumption Physical activity Chemopreventive agents: tamoxifen, an antagonist of the estrogen receptor in breast tissue,Molecular epidemiology,a science that focuses on the contribution of potential genetic and environmental risk factors, identified at the molecular level, to the etiolo

23、gy, distribution and prevention of disease within families and across populations.,What makes us unique. Changes in the number and order of genes (AD) add variety to the human genome.,High-penetrant (外显性）breast cancer susceptibility genes,Brca1 Brca2 P53 PTEN ATM,Presence of BRCA1 and/or BRCA2 gene

24、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 self-breast examination (SBE) encouraged* Presence of BRCA1 and/or BRCA2 gene mutation or strong family history, beginning at age 2

25、5- - CBE every 6-12 months - Self-awareness of changes in the breasts with monthly SBE encouraged - Annual mammography - Annual magnetic resonance imaging Figure 2. 2007 Breast Cancer Screening Guidelines for Women at High Risk,Low-penetrant breast cancer susceptibility genes,Polymorphisms in breast

26、 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.,At nucleotide position 46, there can be an adenine (A)

27、 or a guanine (G) that results in the 16th amino acid in the receptor being arginine or glycine, respectively. The site of the resulting amino acid in the extracellular portion of the receptor is indicated. Similarly, nucleotide substitutions of C to G, G to A, and C to T at nucleotide positions 79,

28、 100, and 491 result in substitutions of glutamine to glutamate, valine to methionine, and threonine to isoleucine at amino acid positions 27, 34, and 164, respectively. Although these examples are for coding nonsynonymous SNPs that change the amino acid sequence, the vast majority of SNPs occur in

29、non-amino acid coding regions of DNA where they have either no effect, or influence transcription factor binding sites, or messenger RNA splicing or stability.,Polymorphism of 2 -adrenergic receptor gene,Candidate polymorphic genes,enzymes implicated in the metabolism of estrogen or various carcinog

30、ens, detoxification of reactive oxygen species （活性氧）emerging from these reactions, alcohol and one-carbon metabolism pathways proteins that play a role in DNA repair or cell signaling processes,Carcinogenesis: The molecular basis of cancer,Nonlethal genetic damage lies at the heart of carcinogenesis

31、. Tumor is monoclonal (单克隆性) Four classes of normal regulatory genes are the principal targets of genetic damage the growth-promoting protooncogenes (原癌基因). the growth-inhibiting tumor suppressor genes (肿瘤抑制基因) genes that regulate programmed cell death (apoptosis) DNA repair genes Carcinogenesis is

32、a multistep process at both the phenotypic and the genetic levels.,Part 2,Figure: Diagram depicting the use of X-linked isoenzyme cell markers as evidence of the monoclonality of neoplasms. Because of random X inactivation, all females are mosaics with two cell populations (with G6PD isoenzyme A or

33、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.,Adapted from Robbins Basic Pathology,G6PD: glucose-6-phosphate dehydrogenase enzyme PGK: phosphoglycerol kinase enzyme,Demonstration of X-Inactivation,Essential alterations for malignant transformation Self-sufficiency in growth signals: EGFR ove