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Somatic Mutations, Germ-Line Mutations, and Breast

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Somatic Mutations, Germ-Line Mutations, and Breast CANCER overview compare: stem cells SOMATIC MUTATIONS, • Class of diseases controlled cell division • Uncontrolled cell division GERM-LINE MUTATIONS, • Spread to adjacent tissues AND BREAST CANCER METASTASIS cancer cells spread by READING: pp. 202-220 bloodstream or lymphatic system BREAST CANCER Carcinoma:Carcinoma: EpithelialEpithelial cells.cells. Most commoncommon formsforms ofof breast,breast, prostate,prostate, lung,lung, coloncolon cancer.cancer. LymphomaLymphoma andand Leukemia:Leukemia: Blood,Blood, bonebone marrow cellscells Sarcoma:Sarcoma: ConnectiveConnective tissue,tissue, oror mesenchymal cellscells Mesothelioma: Mesothelial cellscells lininglining thethe peritoneum,peritoneum, pleura.pleura. Glioma:Glioma: GliaGlia (brain(brain cell)cell) NEW CASES OF CANCER U.S. 2002 Site Number of new cases Skin 800,000 When normal cells are damaged beyond repair, they are eliminated by apoptosis (programmed cell death). Breast (female) 203,500 Prostate 189,000 Lung 169,400 Cancer cells avoid apoptosis and continue to multiply in an uncontrolled manner Colon-rectum 148,300 Urinary system 90,000 Uterus 52,300 Pancreas 30,300 Ovary 23,300 1/31/3 individualsindividuals will olderolder adultsadults -- 1/41/4 ofof allall deathsdeaths duedue toto cancercancer getget somesome formform ofcancerofcancer 1 in 8 women BREAST CANCER SEPARATION OF SOMATIC CELL (some demographics) expected to be LINE AND GERM LINE diagnosed sometime during their lives Breast cancer occurs more often in white + 41,000 US women women than African will die this year AGE American or Asian MUTATIONS women passed on to CONSIDERATIONS progeny, all 12 y - Early menstruation - risk factor (estrogen) tissues, Mendelian 30 y - Late childbearing (1st child) - risk factor (estrogen) usually little effect, 35 y - Breast cancer uncommon below this age cell death for damaged GERM LINE cell; however, all cancers female: eggs (precursors) 40 y - Regular mammograms (yearly) arise from somatic cell male: sperm mutation, one cell confined 40 y - Many breast cancers estrogen-dependent (35%) to one tissue 50 y - Most cancers occur over this age SOMATIC CELLS 55 y - Late menopause - risk factor (estrogen) enviromental stress embryo proper chemical carcinogens 60 y - Risk for breast cancer especially high (NIH website) germ line mutations all tissues radiation (UV, x-ray) 1 normalnormal breastbreast cellscells -- cellcell divisiondivision inin responseresponse BREAST CANCER PROGRESSION toto hormonalhormonal signalingsignaling proliferation metastasis Stage 0: Pre-cancer cells Stage I: Spread to in milk duct lining of breast other breast cells Stage II: Spread out of Stage IV: Metastatic Cancer: breast to lymph node cancer spreads beyond (under the arm) breast and underarm lymph nodes to other tissues, especially bones, lung, liver, brain. Stage III: Locally Advanced Cancer: LOBULAR CARCINOMA DUCTAL CARCINOMA Local treatment: Systemic treatment: large tumor in breast; spread to begins in the lobules of the most common type of breast cancer Surgery, chemotherapy breastbone or other tissues near the mammary glands - begins in the lining of the ducts radiation therapy hormonal therapy breast TUMORS abnormal growth of tissue BENIGN TUMORS CANCEROUS TUMORS Self-contained. Do not spread to other tissues. Not invasive. Cells divide with increasingly more Cause problems by increasing in size aggressive growth until completely until they interfere with the function out of control. Acquire ability to spread of neighboring organs. beyond prescribed boundaries. Cells can detach from primary tumor and move to other sites in the body. Can invade tissues Time line of breast cancer suggesting probable heterogeneity. Primary breast cancers begin as to form new malignant tumors. single (or more) cells which have lost normal regulation of differentiation and proliferation but Single cell + clonal descendants. remain confined within the basement membrane of the duct or lobule. As these cells go through several doublings, at some point they invade through the basement membrane of the ductule or Accumulation of multiple mutations lobule and ultimately metastasize to distant organs. in array of genes (4-7 somatic mutations minimum) CELL PROLIFERATION THE CELL CYCLE Mitosis (M-phase) STOP GO STOP G2 + M GO G1 G1 S G2 Uncontrolled cell Cell division comes from STOP accumulation of genetic suicide S Checkpoints defects that lead to too (programmed cell death) GO much "go" signal, too proto-oncogenes (+) little "stop" signal, and loss of cell suicide proliferationproliferation andand programmedprogrammed cellcell deathdeath tightlytightly regulatedregulated toto ensureensure thethe integrityintegrity ofof organsorgans andand tissuestissues tumor suppressors (-) 2 Tanouye Postdoc Lineage: Reproductive BREAST CANCER GENES Scafe Family System cancer (50s) tumor suppressor genes Male breast Breast cancer (inherited) 10%10% BRCA1 or BRCA2 mutations ~8 % cancer (50’s) BRCA1 or BRCA2 mutations ~8 % BRCA 2 US citizens 11 inin 500500 (q12-13) Askenazi Jews 11 inin 4040 Bilateral All cases under 50 11 inin 1313 breast cancer Under 40 11 inin 1010 (mid-50’s) Ovarian cancer BRCA 1 (early 50’s) (location = D17S74) Daria ? 41y 39y ? ? 34y Ch 13 Ch 17 TUMOR SUPPRESSOR GENES BRCA example pRb was the first ‘classic’ tumor suppressor LOSS-OF-FUNCTION FUNCTION no checkpoint stop; no DNA repair; cell cycle continuously cycles ”STOP” signal The disease; retinoblastoma at cell cycle checkpoint; DNA inherit 2 copies; spontaneous 1 good copy enough repair or apoptosis mutation (85%) (somatic recessive) Retinoblastoma is a cancer which develops in the cells of the retina -one of the less common cancers of childhood (inherited mutation all breast cells) -accounts for only about 3 out of every 100 cancers occurring in children under the age of 15 years STOP Children present with: InheritedInherited BRCA1 mutation 11 inheritedinherited germlinegermline mutation + -an abnormal appearance of the pupil which reflects light as a white reflex, like a breastbreast cancercancer frequencyfrequency + 20%20% byby ageage 40y40y 11 spontaneousspontaneous somaticsomatic mutation cat's eye. 50%50% byby ageage 50y50y -a squint. "TWO-HIT MODEL" 85%85% byby ageage 60y60y "TWO-HIT MODEL" TUMOR-SUPPRESSOR GENE: Rb (Retinoblastoma) (eye tumor example) G1-to-S TRANSITION Inactive Transcription CDK2 Some proteins ALL ARE E2F Factor, E2F CDK4 G1 responsible for CANCER cyclinA progression through GENES Rb cyclinD transition and checkpoint. CDK4/cyclinD complex cyclinE phosphorylates Rb P Rb (retinoblastoma; EF2 inhibitor) S Active Rb P E2F (transcription factor) Transcription E2F p21 Factor, E2F p53 Gene expression: cell progresses through cell cycle E2F CDK enzymes are cyclin-dependent Cyclins are proteins necessary protein kinases; control the activity of for CDK activity other proteins by phosphorylating them target gene 3 DOMINANT ONCOGENE ONCOGENE: RAS ("GAIN-OF-FUNCTION" MUTATION) HORMONE growth factor mutant gene excessive protein or stimulates cell abnormally active protein division HORMONE + RECEPTOR ("always go") SIGNAL TRANSDUCTION CASCADE G-PROTEIN: RAS oncogene signals whether or not hormone present normal gene GO MAP kinase cascade transcription ONE MUTANT COPY AND factor stimulates IT IS A GO = DOMINANT growth CANCER GENES G2-to-M TRANSITION Accumulation of multiple mutations ALL ARE Potential cancer genes - about 100 genes Some proteins CANCER CDC2 1) Inappropriate signals about need for cell division responsible for GENES (homonal signaling pathways: growth factors) cyclinB progression through RAD9 transition and checkpoint. 2) Malfunctions in CDK-cyclin complexes controlling cell cycle transitions 3) Checkpoint breakdowns leading to DNA instability 4) Loss of programmed cell death (cell suicide) 4.
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