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BreastCancer _08-34_

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					                                                                                     CANCER                   overview

                                                                                                                                                          compare: stem cells

           SOMATIC MUTATIONS,                                                               • Class of diseases
                                                                                            • Uncontrolled cell division
                                                                                                                         controlled                                 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: Epithelial cells. Most common forms of breast, prostate, lung, colon cancer.
                                                                                           Carcinoma: Epithelial cells. Most common forms of breast, prostate, lung, colon cancer.
                                                                                           Lymphoma and Leukemia: Blood, bone marrow cells
                                                                                           Lymphoma and Leukemia: Blood, bone marrow cells
                                                                                           Sarcoma: Connective tissue, or mesenchymal cells
                                                                                           Sarcoma: Connective tissue, or mesenchymal cells
                                                                                           Mesothelioma: Mesothelial cells lining the peritoneum, pleura.
                                                                                           Mesothelioma: Mesothelial cells lining the peritoneum, pleura.
                                                                                           Glioma: Glia (brain cell)
                                                                                           Glioma: Glia (brain 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
                           Cancer cells avoid apoptosis and continue to multiply
                                                                                                           Lung                                        169,400
                           in an uncontrolled manner                                                       Colon-rectum                                148,300
                                                                                                           Urinary system                               90,000
                                                                                                           Uterus                                       52,300
                                                                                                           Pancreas                                     30,300
                                                                                                           Ovary                                        23,300
                                                                                                   1/3 individuals will
                                                                                                   1/3 individuals will         older adults - 1/4 of all deaths due to cancer
                                                                                                                                older adults - 1/4 of all deaths due to cancer
                                                                                                   get some form ofcancer
                                                                                                   get some form ofcancer




1 in 8 women                          BREAST CANCER                                              SEPARATION OF SOMATIC CELL
expected to be                                (some demographics)
                                                                                                         LINE AND GERM LINE
diagnosed sometime
during their lives                                   Breast cancer occurs
                                                     more often in white                                                     +
                          41,000 US women            women than African
AGE
                          will die this year         American or Asian                                                                                               MUTATIONS
                                                     women                                                                                                                        passed on to
CONSIDERATIONS                                                                                                                                                                    progeny, all
                                                                                                                                                                                  tissues, Mendelian
 12 y - Early menstruation - risk factor (estrogen)
 30 y - Late childbearing (1st child) - risk factor (estrogen)                        usually little effect,
                                                                                      cell death for damaged                             GERM LINE
 35 y - Breast cancer uncommon below this age                                         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
                              normal breast cells -
                              normal breast cells -
                              cell division in response
                              cell division in response
                                                                                                            BREAST CANCER PROGRESSION
                              to hormonal signaling
                              to hormonal signaling


                                                                                                                                        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
remain confined within the basement membrane of the duct or lobule. As these cells go through
                                                                                                             Single cell + clonal descendants.
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
                                GO
                                                      +                                                                                                                                   M
                                                                                                                                                               G1                         G1
                                                                                                                                                                                          S
                                                                                                                                                                                          G2
         Uncontrolled cell                                                    Cell
         division comes from
         accumulation of genetic                                              suicide                                                            S              STOP        Checkpoints
                                                                                                                                                             GO
                                                                              (programmed cell death)
         defects that lead to too
         much "go" signal, too                                                                                                                                         proto-oncogenes (+)
         little "stop" signal, and
                                            proliferation and programmed cell death tightly
                                            proliferation and programmed cell death tightly
         loss of cell suicide               regulated to ensure the integrity of organs and tissues
                                            regulated to ensure the integrity of organs and tissues
                                                                                                                                                                       tumor suppressors (-)




                                                                                                                                                                                                   2
Tanouye Postdoc Lineage:                                                                             BREAST CANCER GENES
                                                                             Reproductive
Scafe Family                                                                 System cancer
                                                                             (50s)                                tumor suppressor genes


                                              Male breast                                                                       Breast cancer (inherited)   10%
                                              cancer (50’s)                                                                     BRCA1 or BRCA2 mutations ~8 %
                                                                                                                                                                              BRCA 2
                                                                                                                                US citizens        1 in 500
                                                                                                                                Askenazi Jews      1 in 40                    (q12-13)
     Bilateral                                                                                                                  All cases under 50 1 in 13
     breast cancer                                                                                                              Under 40           1 in 10
     (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
                          no checkpoint stop; no DNA repair;
FUNCTION
                          cell cycle continuously cycles
”STOP” signal                                                                                            The disease; retinoblastoma
at cell cycle
                                                                               inherit 2 copies;
checkpoint; DNA                                     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
                                                                                                     -accounts for only about 3 out of every 100 cancers occurring in children
   STOP
                                             (inherited mutation all breast cells)
                                                                                                      under the age of 15 years
                                                                 1 inherited germline mutation
                                                                 1 inherited germline mutation       Children present with:
                            Inherited BRCA1 mutation
                            Inherited BRCA1 mutation
                            breast cancer frequency                            ++                    -an abnormal appearance of the pupil which reflects light as a white reflex, like a
                            breast cancer frequency
                                       20% by age 40y
                                       20% by age 40y           1 spontaneous somatic mutation
                                                                1 spontaneous somatic mutation       cat's eye.
                                       50% by age 50y
                                       50% by age 50y                                                -a squint.
                                       85% by age 60y                "TWO-HIT MODEL"
                                                                     "TWO-HIT MODEL"
                                       85% by age 60y




 TUMOR-SUPPRESSOR GENE: Rb (Retinoblastoma)
                          (eye tumor example)                                                                     G1-to-S TRANSITION
                                                                       Inactive
                                                                       Transcription                           CDK2                               ALL ARE
                                                        E2F            Factor, E2F                                         Some proteins
                 G1                                                                                            CDK4
                                                                                                                           responsible for        CANCER
                                                                                                               cyclinA
                                                         Rb                                                                progression through GENES
                                                                                                               cyclinD
                                                                                                                           transition and checkpoint.
                                 CDK4/cyclinD complex                                                          cyclinE
                                 phosphorylates Rb                                            P
                                                                                                               Rb (retinoblastoma; EF2 inhibitor)
                      S               Active
                                      Transcription
                                                                                    Rb        P                E2F (transcription factor)
                                      Factor, E2F
                                                         E2F                                                   p21
                                                                                                               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
                               excessive protein or         stimulates cell
             mutant gene
                               abnormally active protein
                                                            division                 HORMONE + RECEPTOR
                                            ("always go")                                              SIGNAL TRANSDUCTION
                                                                                                             CASCADE

                                                                                                          G-PROTEIN: RAS
                                                                                                          oncogene signals whether
                                                                                                          or not hormone present


                                           GO
          normal gene                                                                                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)




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posted:10/23/2010
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