Landmarks in Cancer Research: 1961-1990

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1961

• First AACR award, the G. H. A. Clowes Memorial Award, is presented to Renato Dulbecco for meritorious cancer research.

• Triplet code for amino acid translation is deciphered.
  A synthetic RNA molecule consisting entirely of uracil was shown to produce a polypeptide of repeating phenylalanine amino acids. Researchers went on to show how triplets of DNA bases transcribed to RNA are then translated into the individual amino acids of peptides, with different triplets representing the different amino acids, providing the mechanism by which DNA encodes proteins. (59)

• Thelma B. Dunn (right) is the first woman elected as president of the AACR.

1962

• Epidermal growth factor discovered. A heat-stable, antigenic factor responsible for the accelerated development of the incisors and eyelids was identified (which was later called the epidermal growth factor). (60)

1963

• Chemotherapy cures Burkitt lymphoma.
  The geographical distribution of Burkitt lymphoma in parts of sub-Saharan Africa, described in the early 1960s, suggested that it was caused by a vector-transmitted virus. The first successful treatment of a human cancer thought to be caused by a virus, later shown to be Epstein Barr virus, was reported. (61-64)

1964

• RAS is identified.
  Research on RAS began with the first observation that a preparation of a murine leukemia virus isolated from a leukemic rat induced sarcomas in newborn rodents. (65)

• World Medical Association adopts the Declaration of Helsinki for governing research on human subjects.

• Seven physician members of the AACR found the American Society of Clinical Oncology (ASCO).

• U.S. Surgeon General Luther L. Terry publicly affirms that smoking leads to lung cancer.

1965

• Chemoprophylaxis is demonstrated in animal models of chemical carcinogenesis.
  A variety of chemicals were shown to prevent cancer induced by chemicals by activating the detoxification system, competitively inhibiting the carcinogen, preventing initiation of carcinogenesis and other unknown mechanisms. The term chemoprevention was later coined as a new area of focus in cancer research. (66,67)

• Federal Cigarette Labeling and Advertising Act requires printing of warnings on cigarette packs.

1966

• Combination chemotherapy and maintenance treatment prolong remission.
  Preliminary studies of pediatric leukemia had shown synergistic effects of dual-drug treatments. By selecting agents with different side effects, it was proposed that it might be possible to combine several chemotherapy drugs to give greater efficacy without prohibitive toxicity. One of the first of these was MOPP (nitrogen mustard, vincristine, prednisone, and procarbazine), a successful treatment for Hodgkin disease that was described in a study published in Cancer Research. Other combination chemotherapies followed. (68)

• First dedicated mammography machine is developed.
  For several decades prior to the invention of this machine, breast images had been obtained using standard X-ray technology. Subsequent developments allowed for reduced exposure and, eventually, digital mammograms.

• U.S. Surgeon General requires institutional review of clinical research, leading to the establishment of institutional review boards.

1967

• Estrogen receptor is identified.
  Targets in uterine tissue were identified that interact specifically with estrogen. This finding was the first step that led to the detection of estrogen receptors in breast cancers and the design of specific and effective therapies for hormone-dependent breast cancer. (69,70)

1969

• Rhabdomyosarcoma study leads to identification of an inherited familial cancer syndrome.
  A study of children with rhabdomyosarcoma who had relatives who developed other organ-site cancers at an early age led to the identification of a familial cancer syndrome, later shown to be primarily influenced by inherited mutations in p53. (71)

• Tumors are successfully heterotransplanted into athymic “nude” mice.
  Heterotransplantation had only been possible in certain immuneprivileged sites in the mouse, such as the eye chamber, and eventually those grafts were rejected. The removal of the thymus, and thus the T-cell immune response, from young mice permitted transplantation of human tumors into mice for their characterization in a whole organism. (72)

• In situ hybridization is introduced.
  This method enabled detection of the location of specific genes within chromosomes. A wide variety of probes ranging from whole chromosome fluorescent paints to probes for individual genes and gene segments can be used to detect changes in genome copy number, structure, or nuclear location. Combining these with image analysis techniques and multiplex labeling strategies enabled multicolor cytogenetics assays termed SKY or M-FISH in which all human chromosomes can be separately visualized. (73-78)

1970

• Multidrug resistant cell lines are described.
  Resistance to multiple cytotoxic agents is one of the major causes of chemotherapy failure. Research published in Cancer Research would lead to the identification of drug transporters present in the cell membranes that control entry of drugs in and out of the cell and are important for the pharmacokinetics of drug action. (79)

• Reverse transcriptase is identified.
  The discovery of reverse transcriptase had implications for how viruses caused cancer and also challenged the “central dogma” that the transfer of cellular information passed from DNA to RNA to protein, and not in reverse. (80,81)

• Cell cycle is an ordered process.
  By fusing mammalian tissue culture cells at different stages of the cell division cycle and by observing the division of mutant yeast cells under the microscope, it was determined that the order of the cell division cycle is regulated and genes involved in cell cycle regulation were identified and ordered. This work laid the groundwork for the discovery of checkpoint proteins and how cancer cells derail checkpoints. (82-87)

• Chromosome banding technique is developed.
  Q-banding using alkylating fluorochromes allowed individual chromosomes and aberrations therein to be identified with high accuracy. This technique was followed by a large number of different banding chemistries. (88,89)

• DNA restriction enzymes are discovered.
  Restriction enzymes cut DNA at specific and reproducible locations.They would become an important tool in molecular biology, enabling basic characterization of genomes through early mapping techniques prior to sequencing. Once it was determined that they recognized specific sequence motifs surrounding cleavage sites, they would be used for many functions including cloning, transfer, and testing of genes and genotyping. (90)

• U.S. Environmental Protection Agency is formed and provides regulatory enforcement against environmental carcinogens, such as asbestos.

• The U.S. Public Health Cigarette Smoking Act bans advertisements for cigarettes.

1971

• Two-hit hypothesis is proposed.
  Using retinoblastoma as a model and observing patients with one or both eyes affected and those with and without a family history of disease, it was shown how cancer can be caused by two mutational events. In the inherited form of the disease, the first mutation or “hit” occurs in the germline cells and the second in the somatic cells. In the nonhereditary form of the cancer, both “hits” occur in somatic cells over time. (91-93)

• Daughters of mothers who used diethylstilbestrol during pregnancy can develop vaginal cancer.
  Vaginal cancer is rare, particularly in young women. A small group of women ages 14 to 25 with vaginal cancer showed a highly significant association with treatment of their mothers during the first trimester of pregnancy with diethylstilbestrol (DES). In 1971, FDA issued a warning against prescribing DES for pregnant women. Between the time that DES was first manufactured in 1938 and the discovery of health problems in 1971, an estimated 5 to 10 million pregnant women and their children were exposed to the drug. (94)

• President Richard Nixon declares “War on Cancer” in State of the Union Address.

• National Cancer Act of 1971 enables the NCI Director to expand and designate Cancer Centers and Comprehensive Cancer Centers.
  AACR leaders advocated for the passing of the Act and attended the signing at the White House.

• Tumor growth is dependent on angiogenesis.
  Starting from the observation that transplanted tumors that did not grow blood vessels were unable to increase in size, serial experiments demonstrated that tumors secrete factors that encourage new blood vessels to grow into and feed the tumor. Eventually, the genes for these factors would be identified and would become a target for molecular therapies. (95)

• Taxol, a natural plant product, is developed for chemotherapy.
  A component of the Pacific yew tree, Taxol was shown to actively inhibit leukemia cell lines in vitro. The isolated molecule was later produced by chemical synthesis, allowing the increased production necessary for it to be used as a drug treatment. Taxol was approved by FDA in 1992 for treating ovarian cancer and subsequently for breast cancer. (96,97)

• Cells within a tumor can be differentiated into benign cells.
  Shown previously with teratomas (tumors that contain differentiated tissues), it was also demonstrated with squamous cell carcinomas that some cells within a tumor are capable of differentiating into benign cells incapable of forming a tumor when transplanted. This finding, which was published in Cancer Research, supported the idea of a cancer stem cell. (98)

1972

• Bone marrow transplantation is established as a cancer treatment.
  Bone marrow transplants were used to replace blood cell-generating hematopoietic cells in patients with leukemia who had radiation therapy. Initially, transplants were from twin donors and later from donors matched by cell surface antigens. More recently, culturing stem cells extracted from the patient’s blood before treatment has been the method. (99,100)

• Apoptosis, programmed cell death, is triggered by cancer therapies.
  Apoptosis is the process of controlled destruction of unwanted cells, the opposite of cell replication. Cells exhibit characteristic stages of DNA and cytoplasmic condensation, followed by the breaking of the cell into apoptotic bodies and their degradation. Apoptosis can also be triggered by cytotoxic drugs. It would later be shown that tumors can arise from mutations in the apoptosis machinery, making cells resistant to death signals. (101)

• Computerized axial tomography (CAT) scanner is invented.
  Previous imaging techniques had been unable to distinguish between tissues of similar density. The development of the CAT system, which uses a series of sectional X-rays, allowed a greater sensitivity of imaging, particularly for detecting abnormalities in soft tissue. (102)

• Regression models and life tables are applied.
  The Cox regression model and its generalizations represented an important biostatistical advance with application to cancer research as well as many other areas. It affected the conceptualization of follow-up studies in a manner that led to nested case-control and case-cohort sampling methods and other applications relevant to clinical trial design. (103)

1973

• NCI begins the Surveillance, Epidemiology and End Results (SEER) Program, a model for large-scale cancer registries worldwide.

1974

• Errors in DNA replication are responsible for tumor oncogenesis.
  In a study published in Cancer Research, it was proposed that as DNA was synthesized the polymerase might make errors in which bases were incorporated either during replication or repair. These mutations might be the consequence of an error-prone polymerase or the presence of carcinogens. (104)

• First Lady Betty Ford (right) undergoes a mastectomy and speaks publicly about breast cancer.

• Specific chromosome rearrangements are characteristic of types of leukemia.
  Cytogenetics and the evolution of molecular diagnostics for leukemia and lymphoma laid the groundwork for future targeted therapies. The Philadelphia chromosome of chronic myelogenous leukemia, with its characteristic translocation from chromosome 22 to 9, will later be shown to generate the fusion protein Bcr-Abl, against which the molecular treatment imatinib (Gleevec) acts. (105,106)

• DNA cloning methods are developed.
  A method for isolating DNA fragments and introducing them into autonomously replicating bacterial plasmids provided the ability to isolate, identify, and amplify DNA fragments from any organism. The availability of pure and abundant sources of specific DNA fragments enabled the determination of the sequence of bases they contain, and the detection of mutations that cause cancer and heritable diseases. Ultimately, the ability to clone DNA was the basis for determining the sequence of the human and other genomes. (107,108)

1975

• Method is developed to detect specific DNA fragments in mammalian genomes (Southern blotting).
  A method to detect unique sequence genes in complex genomes enabled more precise study of the genetic basis of inherited diseases and cancer. Modifications to the original technique made in 1979 substantially shortened the time needed to do the nucleic acid hybridization and increased the sensitivity to the point that single-copy genes in the human genome could be detected within a few days. (109)

• Bromodeoxyuridine (BrdUrd) labeling techniques are introduced.
  Immunochemical techniques were developed to detect incorporation of BrdUrd labeled nucleotides. This was enabled by development of an antibody against BrdUrd labeled DNA, and later by development of a flow cytometric technique that simultaneously measured DNA content and incorporated BrdUrd. (110,111)

• Monoclonal antibodies are produced.
  By fusing an antibody-deficient myeloma cell with a B cell it was possible to create a line of cells or hybridoma that would produce large quantities of identical or monoclonal antibodies that all recognize the same part of a molecule. Monoclonal antibodies are used in a wide range of applications, diagnostics as well as drug therapies such as trastuzumab (Herceptin). (112)

1976

• Viral oncogenes exist in a related proto-oncogene form in normal cells.
  By using hybridization techniques (because this work occurred before the advent of DNA sequencing), researchers showed that there were forms of cancer-causing viral oncogenes in chicken cells. These were later shown in other species, including mice and humans. (113,114)

• Combination chemotherapy regimen cures pediatric leukemia.
  By applying the previously proved theory of combining chemotherapies in different phases and based on different toxicities, and including radiotherapy, a regimen was developed that prolonged remission in 80% of patients with acute lymphocytic leukemia. (115,116)

1977

• American Cancer Society sponsors first “Great American Smokeout” to curb tobacco use.

• Individual cells within a tumor have different potential for metastasis.
  Taking individual cells from a tumor and transplanting them into mice showed that not all cells are capable of forming new tumors and only some cells within a tumor may be capable of metastasis. (118)

• Tamoxifen is approved for treatment of breast cancer.
  This was the first “antihormone” therapeutic approved by FDA. Building on earlier work on oophorectomy and estrogen removal as a treatment for breast cancer, tamoxifen was shown to inhibit growth of mammary tumors in mice, leading to its approval for treatment of breast cancer. It was also shown that tamoxifen was a selective estrogen receptor modulator, acting in opposition to estrogen in some tissues but acting like estrogen in others. (117)

• RNA splicing is demonstrated.
  That the linear sequence of bases in mRNA results from transcription of a corresponding sequence of DNA had been accepted. New work, first done in viruses and later extended to the cellular genome, showed that mRNA is made from much larger precursors, from which segments are removed by a process called RNA splicing. Alternative splicing patterns are found in many genes to produce different protein products, such as in the p16-ARF locus, which encodes two important tumor suppressors. (119,120)

• Medical magnetic resonance imaging (MRI) scanner is developed.
  The medical MRI allowed sensitive visualization of internal structures without the use of X-rays. MRI provides clearer and more detailed images of the soft tissue structure than other imaging methods, making it an invaluable tool in early diagnosis and evaluation of tumors. (121)

• Inaugural AACR-Richard and Hinda Rosenthal Memorial Award, which recognizes research that has made, or promises to soon make, a notable contribution to improved clinical care in the field of cancer, is presented to Paul P. Carbone.

• First AACR science policy committee, the Public Issues Committee, is formed.

• DNA sequencing is developed.
  The introduction of DNA sequencing led to many advances. Over time, sequencing techniques have been refined and improved to use fluorescent dyes rather than radiolabeling, reduce sample volumes, increase the lengths of sequence read, and use automated robotic systems. (122,123)

1978

• Tobacco-specific nitrosamines are identified as carcinogenic components of cigarette smoke. Nitrosamines derived from nicotine were shown to cause cancer in animal models. These substances would later be shown to contribute to human lung and oral cancers. (124)

1979

• Human homolog of v-gag–myc is discovered.
  Using hybridization studies, the transforming sequence of the avian tumor virus MC29 was identified. This sequence was later named myc, for myelocytomatosis, a virus-induced disease. (125)

• p53 is discovered.
  Discovered as a cellular protein bound by the monkey oncogenic virus SV40, or as a transformation-associated protein in chemically induced tumors, p53 was originally thought to be an oncogene. Later studies showed that it is a tumor suppressor gene that is mutated in the germline of individuals with the Li-Fraumeni cancer predisposition syndrome and in 50% of diverse human tumors. (126-128)

• DNA damage products are detected in human DNA.
  As described in a study published in Cancer Research, DNA adducts were detected in cells incubated with the carcinogen benzo(a)pyrene. The adducts were more common in cells from older persons. The detection of DNA damage products would be useful for identification of carcinogens and in epidemiologic studies. (129-132)

• Tyrosine phosphorylation and protein tyrosine kinases are discovered.
  The discovery of a new type of protein kinase that phosphorylates tyrosine residues in proteins, associated with the polyomavirus middle T antigen transforming protein and the Rous sarcoma virus v-Src oncoprotein, led to the conclusion that dysregulated tyrosine phosphorylation by an activated tyrosine kinase can cause malignant transformation. In subsequent years, inhibitors that target disease-causing tyrosine kinases would be approved for treatment. (133,134)

• Method is developed to detect gene transcripts (Northern blotting).
  Identification of the RNA products of transcription is essential for addressing many biologic problems. The ability to separate RNA by size on gels, transfer it to a solid support, and then detect specific molecules by nucleic acid hybridization provided a critical technical link to enable detection of the transcripts produced by any gene. (135)

• Method is developed to detect specific proteins (Western blotting).
  Establishing how particular genes elicit specific phenotypes requires detection of the protein products encoded by their transcripts. A rapid and sensitive method combining gel electrophoresis for fractionation, and electrophoretic transfer to a solid support for subsequent detection by specific antibodies, enabled this detection. Now proteins can also be detected using mass spectrometry. (136)

• U.S. Department of Health, Education and Welfare creates The Belmont Report, ethical guidelines for research on humans.

1980

• Degradation of collagen in tumor environment promotes metastasis.
  For tumors to metastasize they must pass through the epithelial and endothelial basement membranes and gain access to the bloodstream. Studies showed that tumors secrete proteases that degrade collagen and that cell lines with the highest levels of collagenase had the highest potential for metastasis. (137)

• Prostate specific antigen is a marker for prostate cancer.
  The association of levels of prostate specific antigen with risk for prostate cancer—in a study published in Cancer Research—led to the first routine protein biomarker test used in cancer screening and prevention. (138)

• DNA methylation is shown to be important in cancer.
  Methylation of DNA can prevent a gene from being switched on. Chemotherapy drugs were shown to affect methylation and activate genes, suggesting that targeting methylation of specific genes may provide a way of controlling gene expression and lead to future therapies. It was later demonstrated that the methylation patterns of some genes were different in tumors compared with cells in the same tissue that were not part of the tumor. (139-141)

• Inaugural Award for Outstanding Achievement in Cancer Research, which recognizes a young investigator (not more than 40 years of age) on the basis of meritorious achievement in cancer research, is presented to Malcolm A. S. Moore.

• NCI commissions the National Research Council to review data linking diet and cancer.

1981

• Cell surface antigens of lymphocyte subtypes aid further classification of leukemias and lymphomas.
  A study published in Cancer Research described the development of monoclonal antibodies that recognized specific cell surface receptors characteristic of stages of lymphocyte differentiation. This allowed subclassification of different diseases and more accurate prognosis. (142,143)

• Ubiquitin system for protein degradation is identified.
  How ubiquitin acts as a tagging system to mark proteins that need to be destroyed by the proteosome was demonstrated. Ubiquitination controls proteins involved in many fundamental cell processes important for cancer such as cell cycle, DNA repair, and apoptosis. Later work involved targeting drugs to this pathway as a mechanism to promote apoptosis. (144-146)

• First mouse embryonic stem (ES) cell line is established.
  This technology allows the generation of mouse embryos with directed mutations such as transgenics or knockouts. (147,148)

1982

• The Susan G. Komen Breast Cancer Foundation is founded.

• Proto-oncogenes are involved in cancer.
  Building on earlier work, research showed that the endogenous proto-oncogenes of normal cells could become mutated, becoming oncogenes and causing cancer. (149-151)

• Inaugural Bruce F. Cain Memorial Award, for outstanding preclinical research that has implications for the improved care of cancer patients, is presented to John A. Montgomery.

• Helicobacter pylori is isolated from human stomach ulcers.
  Many decades previously, work had shown viruses involved in causing cancer, but it took years for it to be widely accepted that infection with H. pylori could cause stomach ulcers and that continuous infection and inflammation could result in cancer. (152)

1983

• Human papillomavirus (HPV) is identified as the causative agent of cervical cancer.
  Early epidemiologic work documenting the low incidence of cervical cancer in nuns suggested that the disease might be caused by an infectious agent transmissible by sexual contact. The isolation of HPV DNA from biopsy samples identified the HPV 16 and 18 strains as highly associated with cervical cancer. This work would lead to the development of vaccines to prevent cervical cancer. (153)

• National Academy of Sciences issues report, Diet, Nutrition and Cancer, leading NCI to introduce dietary guidelines to reduce cancer.

• Oncogene cooperation for malignant transformation is demonstrated.
  The observations that normal cells required multiple genetic events to become oncogenically transformed provided a model for the molecular basis for the multistep nature of cancer. (154,155)

• Polymerase chain reaction (PCR) is developed.
  PCR uses a heat-stable DNA polymerase from thermophilic bacteria, allowing replication of multiple copies of a DNA sequence in vitro. This technique permitted an explosion of new methods for cloning, sequencing, and diagnostics and is used in virtually every genetics and molecular biology laboratory. (156)

1984

• Electrospray ionization (ESI) and matrix-assisted laser desorption/ionization (MALDI) techniques are invented.
  These techniques, used in mass spectrometry, allow the analysis of biomolecules such as DNA, proteins, peptides, polymers, dendrimers, and sugars, which were too fragile to be analyzed by more conventional ionization methods. Much of our understanding about biomolecules is dependent on mass spectrometry. (157,158)

• Bcl-2 links apoptosis and cancer.
  Links between Bcl-2 and apoptosis provided the first evidence of a role for programmed cell death in cancer development. (159-164)

1985

• Health Research Extension Act expands NCI mission to include research on the continuing care of patients and their families.

• Lumpectomy is a viable alternative to mastectomy. Clinical studies showed that lumpectomy plus radiation therapy resulted in improved survival compared with radical mastectomy for women with early-stage breast cancer. (165)

1986

• Telomerase is discovered.
  The mechanism of replication at the ends of chromosomes, or telomeres, had been unclear. The discovery of an enzyme capable of synthesizing telomeric DNA onto chromosome ends, thus replenishing them as cells divided, had implications for aging and cancer. (166)

• National Coalition for Cancer Survivorship (NCCS) is founded.

• Retinoblastoma gene, RB, is identified.
  The retinoblastoma gene, RB, was identified in children with hereditary retinoblastoma and shown to be a tumor suppressor gene. (167)

1987

• Her-2/neu receptor is overexpressed in some breast cancers.
  The growth factor receptor gene Her-2/neu was shown to be amplified in approximately 15% of stage I breast cancers. The degree of amplification is associated with decreased survival. This biomarker would later become the target of the highly successful molecular therapy, trastuzumab (Herceptin), improving survival in Her-2/neu-positive patients. (168)

• CTLA-4 gene is discovered.
  A gene encoding the protein CTLA-4 was discovered in a screen for proteins likely to be involved in controlling T-cell activation. This protein went on to be the target of the first cancer immunotherapy of the type known as immune checkpoint inhibitors, which work by taking the “brakes” off the immune system. (169)

• Technique is developed to use homologous recombination in mouse ES cells to create genetically engineered mouse strains.
  Technology to generate mice lacking specific genes, or containing specific mutations, has provided insights into the function of genes involved in development that underlies many inherited diseases and contributes to cancer. Generation of strains with mutations found in human cancers enables modeling of the initiation and progression of cancers in mice that resemble their human counterparts. Such models should prove useful for testing of biologically targeted therapies. (170,171)

1988

• AACR hosts its first Special Conference, “Gene Regulation and Cancer” (Chair: Phillip A. Sharp).
  This in-depth exchange of the latest developments in an emerging area set the tone for future AACR Special Conferences on focused topics, an ongoing series that contributes in a major way to advances in the field.

• AACR launches Women in Cancer Research (WICR), a membership group within the AACR committed to recognizing women’s scientific achievements and fostering their career development and advancement in cancer research.
  The WICR Council acts as an advisory body to the AACR leadership on issues of concern to female investigators and is also responsible for organizing the activities of WICR through its committees.

• Associate Membership, a new category of AACR membership for early-career scientists, is established.
  The Associate Member Council develops programs that address the needs of early-career scientists and acts as an advisory body to the AACR leadership on issues of concern to the next generation of cancer researchers.

• Tumor suppressor genes are mutated in cancer and are the targets of tumor viruses.
  Mutations in tumor suppressor genes have been shown to be responsible for several familial cancers such as retinoblastoma (RB) and Li-Fraumeni syndrome (p53); these genes are also spontaneously mutated in many types of noninherited cancer. They are also the targets of viral oncogenes such as the E1A proteins of adenovirus and E7 of HPV, which bind and inactivate RB. (172-174)

• Adoptive transfer of tumor-infiltrating lymphocytes is first reported to cause tumor regression.
  Lymphocytes were extracted from melanoma tissue from 20 patients with metastatic melanoma, then expanded in vitro before being reinfused back into the patients, leading to tumor regression in 11 of the 20 individuals. (175)

1989

• Original innovation behind the engineering of chimeric antigen receptors on T cells is reported.
  In an effort to direct T cells, researchers generated a chimeric T-cell receptor, composed of its constant domain and an antibody’s variable domains, such that the chimeric receptor activates the T cell when it recognizes antigen specific to the antibody domains. This molecular innovation served as a foundation for the increasing number of FDA-approved chimeric antigen receptor T cell-based therapies. (176)

1990

• Americans with Disabilities Act protects cancer survivors against discrimination in the workplace.

• AACR adds a second journal to its publishing program, Cell Growth & Differentiation (succeeded in 2002 by Molecular Cancer Research).

• Specific molecular alterations are correlated with stages of cancer progression.
  Expanding on the two-hit hypothesis of carcinogenesis in colorectal tumors, researchers showed that a number of events occurred, including activation of oncogenes and inactivation of tumor suppressor genes, totaling mutations in at least four to five genes, which influenced progression from a benign polyp to a large metastatic malignant tumor. (177)

• BRCA1 mutations are associated with breast cancer.
  The identification of gene variants associated with a family history of breast cancer allowed screening of high-risk women and the choice for those with known increased risk to take preventive measures such as tamoxifen therapy or mastectomy. (178)

• Breast and Cervical Cancer Mortality Prevention Act provides grants to improve programs for breast and cervical cancer prevention.

• San Luis Obispo, California, becomes the first city in the world to ban smoking in all public buildings.

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