Causes of Cancer
 Philadelphia chromosome – translocation between chromosomes 9 and 22 (piece of 22 on 9) that gives rise to
CML (chronic myelogenous leukemia)
 Cancer – group of disease where cells no longer respond to normal restraints on growth
o Normal cells stop proliferating with cell-cell contact (contact inhibition)
o Cancer cells don’t require growth-stimulatory signals and are resistant to growth-inhibitory signals
o Have infinite proliferative capacity and don’t become senescent
o Lose anchorage dependence (can grow without support of ECM or structural support)
 Patients with leukemia experience various hemorrhagic manifestations caused by decreased number of platelets
o Because of uncontrolled proliferation of WBCs within limited space of marrow, megakaryocytes in
marrow squeezed and fail to develop into mature platelets
o Number of mature thrombocytes in circulation falls, and thrombocytopenia develops
 Malignant neoplasms of epithelial cell origin called carcinomas
 If cancer grows in gland-like pattern, they are adenocarcinomas
 Melanocarcinoma or melanoma – carcinoma arising from melanocytes
 Criteria for cells to be classified “transformed” (from benign to cancerous)
o Serum in cell culture medium stimulates cell growth
 Transformed cells have reduced requirement for serum (liquid fraction of clotted blood that
contains factors for cell proliferation)
o Ability to grow without attachment to supporting matrix (can grow suspended in soft agar mixture)
o Ability of cells to form tumors when injected into mice that lack immune system
 For every gene that causes cancer (oncogene), there is a corresponding cellular gene (proto-oncogene)
o Ras oncogene comes from c-ras proto-oncogene; found in bladder carcinoma, lung and colon tumors
 Common wart is benign tumor formed from slowly expanding mass of cells; nevi are tumors of skin formed by
melanocytes that have been transformed from highly dendritic single cells interspersed among other skin to
round oval cells that grow in aggregates (nests)
 Malignant neoplasm is proliferation of rapidly growing cells that progressively infiltrate, invade, and destroy
surrounding tissue
 Tumors develop angiogenic potential
 Transformation of normal cell to cancer cell begins with damage to DNA; mutations result from damaged DNA
not repaired properly or not repaired before replication
o When cell with one mutation proliferates, clonal expansion results in substantial population of cells
containing this mutation
o With each clonal expansion, probability of another transforming mutation increases
o Because mutations accumulate in genes that control proliferation, subsequent mutations occur even
more rapidly until cells acquire multiple mutations necessary for full transformation
 Transforming mutations occur in genes that regulate cell proliferation and differentiation (proto-oncogenes),
suppress growth (tumor suppressor genes), tell irreparably damaged cells to apoptosis, or repair damaged DNA
Damage to DNA Leading to Mutations
 Alteration in chemical structure of DNA (sequence of bases in gene) absolute requirement for development of
cancer; function of DNA depends on presence of polar chemical groups in DNA bases
o O and N atoms in DNA bases are targets for various electrophiles
 Chemical carcinogens generally stable lipophilic compounds that must be activated by metabolism in body to
react with DNA
o Many chemotherapeutic agents (designed to kill proliferating cells by interacting with DNA) may act as
carcinogens and cause new mutations and tumors while eradicating the old
 Exposure to radiation and UV light causes formation of pyrimidine dimers (can cause all types of skin cancer)
o Wavelength of UV light most associated with skin cancer is UVB, which forms pyrimidine dimers
o Pyrimidine dimers repaired by nucleotide excision repair pathways that require products of at least 20
genes; excessive exposure to sun, and nucleotide excision repair pathway overwhelmed and some
damage remains unrepaired
 Proto-oncogenes converted to oncogenes by mutations in DNA that cause gain of function
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Radiation and chemical carcinogens act by causing mutation in regulatory region of gene, increasing rate
of production of proto-oncogene protein, or by producing mutation in coding portion of oncogene that
results in synthesis of protein of slightly different amino acid composition capable of transforming
o Entire proto-oncogene or portion of it may be transposed or translocated; in new location, protooncogene may be under control of promoter that is regulated differently, allowing the gene to be
expressed in tissue where it is not normally expressed or at higher-than-normal levels of expression
 If only portion of proto-oncogene translocated, it may be expressed as truncated protein with
altered properties or may fuse with another gene and produce a fusion protein
 Truncated or fusion protein may be hyperactive and cause inappropriate cell growth
o Proto-oncogene may be amplified so multiple copies of gene produced in single cell; if more genes
active, more proto-oncogene protein will be produced, increasing growth rate of cells
 Oncogene N-myc (cell proliferation transcription factor related to c-myc) amplified in some
neuroblastomas
 Amplification of erb-b2 oncogene (growth factor receptor) seen in several breast cancers
o If oncogenic virus infects cell, its oncogene may integrate into host cell genome, permitting production
of abnormal oncogene protein; cell may be transformed and exhibit abnormal pattern of growth
 Virus can insert strong promoter into host cell genome, which may cause increased or untimely
expression of normal proto-oncogene
 Burkitt lymphoma – general name for several types of B-cell malignancies; results form translocation between
chromosomes 8 and 14; translocation moves proto-oncogene transcription factor c-myc to chromosome 14,
where it becomes under control of promoter region for immunoglobulin heavy-chain gene, which leads to
inappropriate and overexpression of c-myc
o Results in uncontrolled cell proliferation and tumor development
o All subtypes contain this translocation
o Epstein-Barr virus infection of B cells associated with certain types of Burkitt lymphoma
 Errors repaired before replication don’t become mutagenic (thank you, DNA repair enzymes)
 Inherited mutations in tumor suppressor genes BRCA1 and BRCA2 predispose women to development of breast
cancer; protein products of these genes play roles in DNA repair, recombination and regulation of transcription
 HNPCC (hereditary nonpolyposis colorectal cancer) results from inherited mutations in enzymes involved in DNA
mismatch repair systems
 Philadelphia chromosome creates fusion protein that contains N-terminal region of Bcr protein from
chromosome 22 and C-terminal region of Abl protein from chromosome 9
o Abl is proto-oncogene, and resulting Bcr-Abl loses regulatory region and is constitutively active, resulting
in deregulated tyrosine kinase activity
o When active Abl stimulates Ras pathway of signal transduction, leading to cell proliferation
Oncogenes
 Proto-oncogenes encode proteins that are growth factors, growth factor receptors, signal transduction proteins,
transcription factors, cell cycle regulators, and regulators of apoptosis
 Nomenclature – oncogene is lowercase and italics (myc) while protein product is capitalized only (Myc)
 Mutations in oncogenes that give rise to transformation usually gain-of-function mutations
 miRNAs can behave as oncogenes if overexpressed (increased function) if its target (which would exhibit
reduced expression) is protein involved in inhibiting cell proliferation
 Growth factors bind to cellular receptors on PM and stimulate signal transduction pathway that activates
transcription of certain genes; if too much growth factor or growth factor receptor, target cells respond by
proliferating inappropriately
o Growth factor receptors may become oncogenic through translocation or point mutations in domains
that affect binding of growth factor, dimerization, kinase activity, or some other aspect of signal
transmission; receptor transmits proliferative signal even without normal ligand
o Gene for human epidermal growth factor receptor overexpressed in 10-20% of breast cancer cases;
prognosis poor because patients display shorter disease-free intervals, increased risks for metastasis,
and resistance to therapy
 Herceptin – monoclonal antibody with specificity for HER2 protein on receptor; blocks
receptor’s action; not all tumors responsive to herceptin
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Genes that encode proteins involved in growth factor signal transduction cascades may be proto-oncogenes
o Binding of growth factor leads to activation of Ras; when Ras binds GTP, it is active, but Ras slowly
inactivates itself by hydrolyzing bound GTP to GDP and Pi, controlling length of time Ras active
 Ras, when active, activates Raf (MAP kinase kinase kinase), which activates MEK (MAP kinase
kinase), which activates MAP kinase
 Activation of MAP kinase results in phosphorylation of cytoplasmic and nuclear proteins,
followed by increased transcription of transcription factor proto-oncogenes myc and fos
 Mutations in genes for any proteins that regulate MAP kinase activity, as well as proteins
induced by MAP kinase activation, can lead to uncontrolled cell proliferation
 Many transcription factors (Myc and Fos) are proto-oncoproteins (products of proto-oncogenes)
o MAP kinase induces myc and fos as well as directly activates AP-1 transcription factor through
phosphorylation
o AP-1 is heterodimer formed by protein products of fos and jun families of proto-oncogenes
o Targets of AP-1 activation are genes involved in cellular proliferation and progression through cell cycle
(as are targets of myc transcription factor)
o Synthesis of transcription factor C-myc tightly regulated in normal cells; expressed only during S phase of
cell cycle
 In large numbers of tumor types, regulated expression lost, and c-myc becomes inappropriately
expressed or overexpressed throughout cell cycle, driving cells to continuously proliferate
o Net result of alterations in transcription factors is increased production of proteins that carry out
processes required for proliferation
 Activators of DNA replication and cell division work through cyclins and cyclin-dependent kinases (CDKs) that
control progression from one phase of cycle to another
o CDKs made constantly throughout cell cycle but require binding of specific cyclin to be active
o Different cyclins made at different times in cell cycle control each transition (G1/S, S/G2, G2/M)
o Activity of cyclin-CDK complex regulated through phosphorylation and inhibitory proteins (CKIs)
 CKIs slow cell cycle progression by binding and inhibiting cyclin-CDK complexes
o CDKs controlled through activating phosphorylation by CAKs and inhibitory hyperphosphorylation
kinases
 At G1/S checkpoint – because cell committed to DNA replication and division once it enters S phase, multiple
regulatory proteins involved in determining whether cell ready to pass this checkpoint
o In quiescent cells, Rb (retinoblastoma gene product) complexed with E2F (group of transcription factors
collectively called this), resulting in inhibition of E2F family
o Upon growth factor stimulation, cyclin Ds induced and bind to cdk4 and cdk6 (produced throughout cell
cycle), converting them to active protein kinases)
o One of targets of cyclin/CDK phosphorylation is Rb protein, which releases it from E2F, and E2F free to
activate transcription of genes required for entry into S
 Rb protein is tumor suppressor gene
o Proteins induced by E2F include cyclin E, cyclin A, cdc25A (activating protein phosphatase), and proteins
required to bind at origins of replication to initiate DNA synthesis
 Synthesis of cyclin E allows it to complex with cdk2, which hyperphosphorylates Rb protein,
keeping Rb in inactive state
 Cyclin A complexes with Cdk2, which phosphorylates and inactivates E2F family, ensuring signals
not present for extended periods of time
o Progression through cell cycle opposed by CKIs
 CKIs regulating cyclin/CDK expression in G1 phase are either in Cip/Kip family or INK4 family
 Cip/Kip family members have broad specificity and inhibit all cyclin-CDK complexes
 INK4 family specific for cyclin D-cdk4/6 family of complexes
 Some CKIs induced by DNA damage to cell and halt cell cycle progression until damage can be
repaired (CKI p21 responds to specific signals to block cell proliferation)
 If damage can’t be repaired, cell undergoes apoptosis
Tumor Suppressor Genes
 Tumor suppressor genes encode proteins that inhibit proliferation in response to certain signals (DNA damage)
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o Signal removed when cell fully equipped to proliferate
o Can affect cell cycle regulation, signal transduction, transcription, and cell adhesion
o Products frequently modulate pathways activated by products of proto-oncogenes
Tumor suppressor genes contribute to development of cancer when both copies of gene inactivated (different
from proto-oncogenes and miRNAs because only one of them needs to be mutated to initiate transformation)
o miRNAs can be either oncogenes (overexpression) or tumor suppressors (loss of function) depending on
genes they regulate
Rb functions in transition from G1 to S phase and regulates activation of E2F; if person inherits mutated copy of
rb allele, that person will develop retinoblastoma because of high probability that second allele of rb will gain
mutation (familial retinoblastoma)
o Those who develop rb mutation on their own have sporadic retinoblastoma and acquire 2 specific
mutations during their lifetime
p53 protein – transcription factor that regulates cell cycle and apoptosis; p53 halts replication in cells that have
suffered DNA damage and targets unrepaired cells for apoptosis
o In response to DNA-damaging mutagen, level of p53 rises and stimulates transcription of p21 (member
of Cip/Kip family of CKIs); p21 gene product inhibits cyclin-CDK complexes, preventing phosphorylation
of Rb and release of E2F proteins, preventing cell from entering S phase
o p53 stimulates transcription of DNA repair enzymes (i.e., GADD45)
o If DNA successfully repaired, p53 induces its own downregulation through activation of mdm2 gene; if
DNA repair not successful, p53 activates Bax and IGF-BP3, involved in apoptosis
 IGF-BP3 protein product binds receptor for insulinlike growth factor, which induces apoptosis by
blocking antiapoptotic signaling by growth factors, and cell enters growth factor deprivation
o Inheritance of mutation in p53 leads to Li-Fraumeni syndrome (characterized by multiple types of
tumors)
 Mutations in p53 present in more than half tumors, which are secondary mutations within cell
 If p53 mutated, overall rate of cellular mutation will increase because there is no p53 to check
for DNA damage, initiate repair of damaged DNA, or initiate apoptosis if damage not repaired
Ras family of proteins involved in signal transduction for many hormones and growth factors; activity of
pathways interrupted by GAPs, which vary among cell types
o Neurofibromin (product of tumor suppressor gene NF-1) is nervous system-specific GAP that regulates
activity of Ras in neuronal tissues; growth signal transmitted so long as Ras protein binds GTP
 Binding of NF-1 to Ras activates GTPase domain of Ras, which hydrolyzes GTP to GDP,
inactivating it
 Without functional neurofibromin molecule, Ras perpetually active
o Inherited mutation in NF-1 can lead to neurofibromatosis (disease primarily of numerous benign painful
tumors of nervous system)
Patched and smoothened coreceptor genes encode receptor for hedgehog class of signaling peptides
o Coreceptors normally function to control growth during embryogenesis
o Patched receptor protein inhibits smoothened (its coreceptor protein)
o Binding of hedgehog ligand to patched releases inhibition of smoothened, which transmits activating
signal to nucleus, stimulating new gene transcription
o Smoothened is proto-oncogene, and patched is tumor suppressor gene
o If patched loses function, smoothened can signal cell to proliferate, even in absence of hedgehog
o If smoothened undergoes gain-of-function mutation, it can signal in absence of hedgehog signal, even in
presence of patched
o Inherited mutations in either will lead to increased incidence of basal cell carcinoma
Cadherin family of glycoproteins mediates calcium-dependent cell-cell adhesion; form intercellular complexes
o Anchored intracellularly by catenins, which bind to actin filaments
o Loss of E-cadherin expression contributes to ability of cancer cells to detach and migrate (metastasis)
 Individuals who inherit mutation in E-cadherin (CDH1) predisposed to developing diffuse-type
gastric cancer
o Catenin proteins also act as transcription factors
o β-catenin binds to complex that contains regulatory protein (APC), activating it for degradation
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When appropriate signal inactivates APC, β-catenin levels increase, and it travels to nucleus
where it activates myc or cyclin D1 transcription, leading to cell proliferation
o APC is tumor suppressor gene; if inactivated, it can’t bind β-catenin and inhibit cell proliferation
 Mutations in APC or proteins that interact with it found in most sporadic colon cancers
 Inherited mutations lead to familial adenomatous polyposis (FAP)
Cancer and Apoptosis
 After apoptosis, phosphatidylserine (lipid on inner leaflet of PM) exposed on external surface of apoptotic
vesicles and is one of phagocytic markers recognized by macrophages and other nearby phagocytic cells
 Apoptosis divided into initiation phase, signal integration phase, and execution phase
o Can be initiated by death receptors (TNF), deprivation of growth hormones, mitochondrial damage, and
irreparably damaged DNA
o Signal integration phase balances proapoptotic signals against antiapoptotic cell survival signals by
members of Bcl-1 family of proteins
o Execution phase carried out by caspases
 Caspases present in cell as procaspases; divided into initiator caspases (specifically cleave other procaspases)
and execution caspases (cleave other cellular proteins involved in maintaining cellular integrity)
o Initiator caspases activated through death receptor pathway and mitochondrial integrity pathway;
activate execution caspases, which cleave protein kinases involved in cell adhesion, lamins that form
inner lining of nuclear envelope, actin and other cell structure proteins, and DNA repair enzymes
o Cleave inhibitor protein of endonuclease CAD, activating it to initiate degradation of cellular DNA
o With destruction of nuclear envelope, Ca2+ and Mg2+-dependent endonucleases also activated
 Death receptors subset of TNF-1 receptors that includes Fas/CD95, TNF-R1, and DR3
o Receptors form trimer that binds TNF-1 or another death ligand on external domain and binds adaptor
proteins to intracellular domain
o Activated TNF-receptor complex forms scaffold binding 2 molecules of procaspase 8 (or procaspase 10),
which autocatalytically cleave each other to form active caspase
 Caspases 8 and 10 are initiator caspases that activate execution caspases 3, 6, and 7
o Caspase 3 also cleaves Bcl-2 protein (Bid) to form that activates mitochondrial integrity pathway
 Growth factor withdrawal, cell injury, release of certain steroids, and inability to maintain low levels of
intracellular Ca2+ all lead to release of cytochrome c from mitochondria
o Cytochrome c loosely bound to outside of inner mitochondrial membrane; release initiates apoptosis
o In cytosol, cytochrome c binds Apaf; Apaf/cytochrome c complex binds caspase 9 (initiator) to form
active apoptosome complex, which activates execution caspases (3, 6, and 7) by zymogen cleavage
 Bcl-2 family members decision makers that integrate pro-death and anti-death signals to determine whether cell
should undergo apoptosis; both pro-apoptotic and anti-apoptotic members of Bcl-2 family exist
o Anti-apoptotic factors contain all 4 domains (BH1-BH4), channel-forming pro-apoptotic factors contain
BH1-BH3, and prop-apoptotic BH3-only family members
o Anti-apoptotic Bcl-2-type proteins (Bcl-2, Bcl-L, and Bcl-w) can either insert into outer mitochondrial
membrane to antagonize channel-forming pro-apoptotic factors (decreasing cytochrome c release) or
can bind cytoplasmic Apaf so it can’t form apoptosome complex
o Ion channel-forming members (such as Bax) don’t contain binding factor for Apaf, so when they
dimerize with BH3-only members in outer mitochondrial membrane, they form ion channel that
promotes cytochrome c release rather than inhibiting it
o BH3-only proteins (Bim and Bid) contain only structural domain that allows them to bind other Bcl-2
family members and not domains for binding to membrane, forming ion channels, or binding to Apaf
 Binding activates pro-death family members and inactivates anti-apoptotic members
o When cell receives signal from pro-death agonist, BH3 protein (like Bid) activated, which then activates
Bax (ion-channel-forming), which stimulates release of cytochrome c
 At same time Bid is activating Bax, it binds Bcl-2, disrupting Bcl-2/Apaf complex, freeing Apaf to
bind to released cytochrome c to form apoptosome
o When Bcl-2 mutated, it is usually overexpressed (i.e., in follicular lymphoma or CML); overexpression
disrupts normal regulation of pro-apoptotic and anti-apoptotic factors in favor of anti-apoptotics,
leading to inability to destroy cells with damaged DNA
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Bcl-2 is multidrug-resistant transport protein and, if overexpressed, will block induction of
apoptosis by antitumor agents by rapidly removing them from cell
 Activation of growth factor-dependent signaling pathways that inhibit apoptotsis, such as PDGF/Akt/BAD
pathway can cause apoptosis-resistance in cancer cells
o Nonphosphorylated BAD acts like Bid in promoting apoptosis; binding of PDGF to receptor activates PI-3
kinase, which phosphorylates and activates serine-threonine kinase Akt
o Activation of Akt results in phosphorylation of pro-apoptotic BH3-only protein BAD, which inactivates it
o One of features of neoplastic transformation is loss of growth factor dependence for survival
o MAP kinase pathway sends cell survival signals
o MAP kinase kinase phosphorylates and activates RSK, which phosphorylates BAD and inhibits its activity
o Gain-of-function mutations in genes that control these pathways (such as ras) create apoptosis-resistant
cells
 Bcl-2 levels regulated by miRNAs (miR-15 and miR-16); if expression of these miRNAs altered, Bcl-2 levels
altered, promoting either apoptosis (if Bcl-2 levels decrease) or cell proliferation (if Bcl-2 levels increase)
o Loss of both miRNAs found in majority of chronic lymphocytic leukemia (CLL) cells
o Loss of miR-15 and miR-16 expression leads to increase in Bcl-2 levels, favoring cell proliferation
 miR-21 regulates expression of PDCD4, which is upregulated during apoptosis and blocks translation
o Loss of miR-21 activity leads to cell death (PDCD4 would be overexpressed)
o Overexpression of miR-21 would be anti-apoptotic (PDCD4 expression ablated)
 miR-17 cluster regulates PKB/akt pathway by regulating levels of PTEN (enzyme that converts PIP3 to PIP2), as
well as levels of E2F family
o Upregulation of miR-17 would decrease PTEN levels, and cellular proliferation favored because of
constant activation of akt pathway
Cancer Requires Multiple Mutations
 Single change in one oncogene or tumor suppressor gene not adequate for transformation
o If cells derived from biopsy specimens of normal cells not immortalized (able to grow in culture
indefinitely), addition of ras oncogene to cells not sufficient for transformation; additional mutations in
combination of oncogenes (ras and myc together) can result in transformation
o 4-7 mutations required for normal cells to be transformed
 Cells accumulate multiple mutations through clonal expansion; when DNA damage occurs in normally
proliferative cell, population of cells with that mutation produced; expansion of mutated population increases
probability of second mutation in cell containing first mutation
o After one or more mutations in proto-oncogenes or tumor suppressor genes, cell may proliferate more
rapidly in presence of growth stimuli and further mutations grow autonomously (independent of normal
growth controls)
o Enhanced growth increases probability of further mutations
At the Molecular Level, Cancer is Many Different Diseases
 Particular type of cancer can arise in multiple ways (patched and smoothened are receptor and coreceptor for
signaling peptide sonic hedgehog; mutation of smoothened or inactivation of patched can give rise to basal cell
carcinoma)
 TGF-β and its signal transduction proteins Smad4/DPC part of same growth-inhibiting pathway; either may be
absent in colon cancer
 Treatments successful in some patients may not work in others because of these types of variations
 Treatment for CML – fusion protein Bcr-Abl found only in transformed cells that express Philadelphia
chromosome and not in normal cells
o Gleevec – drug designed to specifically bind to and inhibit only active site of fusion protein, not normal
proteins; stops cell proliferation, and induces apoptosis in some cells
o Some patients suffered relapses and Bcr-Abl proteins in these patients had single amino acid
substitution near active site that prevented Gleevec from binding to protein
o Other tyrosine kinase inhibitors (dasatinib and nilotinib) can be used in treating CML if resistance to
Gleevec encountered
Viruses and Human Cancer
 HTLV-1, HIV, and hepatitis C – retroviruses associated with development of cancer
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Hepatitis B, Epstein-Barr virus (EBV), HPV, and herpes (HHV-8) – DNA viruses associated with cancer
HTLV-1 causes adult T-cell leukemia; HTLV-1 genome encodes protein Tax, which is a transcriptional coactivator
o Cellular proto-oncogenes c-sis and c-fos activated by Tax, altering normal controls on cellular
proliferation and leading to malignancy, making tax a viral oncogene
 HIV infection leads to immunosuppression, and consequently, loss of immune-mediated tumor surveillance
o HIV-infected individuals predisposed to non-Hodgkin lymphoma, which results from overproduction of
T-cell lymphocytes
o HIV genome encodes Tat (transcription factor that activates transcription of IL-6 and IL-10 genes in
infected T cells
o IL-6 and IL-10 are growth factors that promote proliferation of T cells, and their increased production
contributes to development of non-Hodgkin lymphoma
o Tat can be released from infected cells and act as angiogenic growth factor, contributing to
development of Kaposi sarcoma
 Chronic hepatitis B infections lead to hepatocellular carcinoma
 EBV associated with B-cell and T-cell lymphomas, Hodgkin disease, and other tumors
o EBV encodes Bcl-2 protein that restricts apoptosis of infected cell
 HHV-8 associated with Kaposi sarcoma
Biochemical Comments
 TNM system standardizes classification of tumors: T (stage of tumor; the higher the number, the worse the
prognosis), N (number of lymph nodes affected by tumor), and M (presence of metastasis; 0 for none, 1 for
presence of metastatic cells)
 Mutations associated with malignant melanomas include ras (gain of function in growth signal transduction
oncogene), p53 (loss of function of tumor suppressor gene, p16 (loss of function in Cdk inhibitor tumor
suppressor gene), Cdk4 (gain of function in cell cycle progression oncogene), and cadherin/ β-catenin regulation
(loss of regulation that requires attachment)
 HNPCC and hereditary breast cancer both result from inherited mutations in genes involved in DNA repair
o HNPCC can be caused by any of 5 mutations in genes that play role in DNA mismatch repair (all act as
tumor suppressors, so loss of function required for tumor to develop)
 Lack of DNA mismatch repair enzyme doesn’t directly lead to cancer (such as activating mutation in myc would)
o Lack of functional mismatch repair system increases frequency at which new mutations introduced into
somatic cells (particularly rapidly proliferating cells such as colonic epithelium), such that eventually
mutation will result in gene necessary for proper growth control
 Familial breast cancer traced to inherited mutations of BRCA1 and BRCA2
o BRCA1 acts as tumor suppressor; biochemical function is to participate in response to DNA damage
 Phosphorylated by various kinases, each of which activated by different form of DNA damage
 Primarily involved in repairing double-strand breaks in DNA and transcription-coupled repair
 Once BRCA1 phosphorylated, it signals for cell cycle arrest to allow DNA damage to be repaired
 Women with BRCA1 mutation have 80% risk of developing breast cancer and 40% risk of
developing ovarian cancer; men with BRCA1 mutation don’t develop breast cancer
o BRCA2 required for DNA double-strand break repair, usually caused by ionizing radiation
 Loss of activity required for cancer to develop (tumor suppressor)
 Required for homologous recombination between sister chromatids during meiosis and mitosis
 Linked to increased incidence of breast cancer in both men and women; increased ovarian
cancer in women
 PARP-1 inhibitors being tested to be used for treatment of BRCA1 and BRCA2-induced breast cancers
o Double-strand break repair occurs either by homologous recombination (requiring activities of BRCA1
and BRCA2 proteins) or through non-homologous end-joining (NHEJ; error-prone process caused by
trimming of DNA ends before ligation)
o Single-strand breaks in DNA more common than double-strand breaks; cellular repair mechanism
dependent on PARP-1, which produces large branched chains of poly (ADP-ribose) (derived from NAD+)
at site of damage, which acts as docking station for proteins involved in repairing single-strand break
 Inhibiting PARP-1 leads to accumulation of single-strand breaks in DNA
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PARP-1 inhibitors effective in killing BRCA1 or BCRA2 mutated cells in that when single-strand breaks not
repaired, they’re often converted to double-strand breaks when replisome tries to replicate through
break; in cell lacking BRCA1 or BCRA2 activity, only way DNA can be repaired is by NHEJ, which is errorprone process, leading to cells accumulating large number of mutations, eventually leading to cell death
Cells with functional BRCA1 and BRCA2 activity don’t die