We review and discuss data on the genetic alterations documented in human breast carcinomas at the molecular level. These alterations may result in: 1) deletion of genetic material (chromosome 11p, 13q, 3p, 1q, 17p); 2) amplification of genes or entire chromosomal segments (c-myc, c-erb-B2, locus DF3/PUM, loci on 11q13); 3) rearrangements (c-myc); 4) point mutations (c-ras). Presently available informations do not allow the development of cohesive pathogenetic models but indicate that the molecular basis of human breast cancer is heterogeneous.
Get full access to this article
View all access options for this article.
References
1.
AaronsonS.A., TronickS.R.: The role of oncogenes in human neoplasia. In: Important Advances in Oncology 1985, De VitaV.T., HellmanW., RosenbergS.A. (eds.), pp. 3–15, J.B. Lippincott, Philadelphia, 1985.
2.
AdelaideJ., MatteiM.G., MariesI., RaibaudF., PlancheJ., De LapeyriereQ., BirnhaumD.: Chromosomal localization of the hst oncogene and its coamplification with the int-2 oncogene in a human melanoma. Oncogenes, 2: 413–416, 1988.
3.
AliI.U., LidereauR., TheilletC., CallahanR.: Reduction to homozygosity of genes on chromosome 11 in human primary breast neoplasia. Science, 238: 185–188, 1987.
4.
AliI.U., LidereauR., CallahanR.: Heterogeneity of genetic alterations in primary human breast tumors. In: Breast Cancer: Cellular and Molecular Biology.LippmanM.E., DicksonR.B. (eds.), Kluwer, Boston, 1988.
5.
AliI.U., CampbellG., LidereauR., CallahanR.: Amplification of c-erb B2 and aggressive human breast tumors. Science, 240: 1795–1796, 1988.
6.
AliI.U., CampbellG., LidereauR., CallahanR.: Lack of evidence for the prognostic significance of c-erb B2 amplification in human breast carcinoma. Oncogene Research, 3: 1–8, 1988.
7.
AliI.U., MerloG., LidereauR., CallahanR.: The amplification unit on chromosome llql3 in aggressive primary human breast tumors entails the bcl-1, int-2 and hst loci. Oncogene, 4: 89–92, 1989.
8.
AliI.U., CampbellG., MerloG., SmithG., CallahanR., LidereauR.: Multiple genetic alterations in human breast cancer and their possible prognostic significance. Cancer Cell, Vol. 7, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., in press, 1989.
9.
AlitaloK., SchwabM.: Oncogene amplification in tumor cells. Adv. Cancer Res., 47: 235–281, 1986.
10.
AtkinN.: Chromosome 1 aberration in cancer. Cancer Genet. Cytogenet., 21: 279–285, 1986.
11.
BargmannC.I., HungM.C., WeinbergR.A.: Multiple independent activations of the neu ncogene by a point mutation altering the transmembrane domain of pl85. Cell, 45: 649–657, 1986.
12.
BassinR.H., NodaM.: Oncogene inhibition by cellular genes. In: Advances in viral oncology, KleinG. (ed.), vol. 6, pp. 103–127, Raven Press, New York, 1987.
13.
BenedictW.F., WeissmanB.E., MarkC., StanbridgeE.J.: Tumorigenicity of human HT1080 fibrosarcoma x normal fibroblast hybrids: chromosome dosage dependency. Cancer Res., 44: 3471–3479, 1984.
14.
BergerM.S., LocherG.W., SaurerS., GullickW.J., Water-fieldM.D., GronerB., HynesN.: Correlation of c-erbB2 gene amplification and protein expression in human breast carcinoma with nodal status and nuclear grading. Cancer Res., 48: 1238–1243, 1988.
15.
BishopJ.M.: Cellular oncogenes and retroviruses. Ann. Rev. Biochem., 52: 301–354, 1983.
16.
BonillaM., RamirezM., Lopez-CuetoJ., GariglioP.: In vivo amplification and rearrangement of c-myc oncogene in human breast tumors. J. Natl. Cancer Inst., 80: 665–671, 1988.
17.
BrauschH., JohnsonB., HovisJ., YanoT., GazdarA., PettingilO., GrazianoS., SorensonG., PoieszB., MinnaJ., LinehanM., ZbarB.: Molecular analysis of the short arm of chromosome 3 in small-cell and non small-cell carcinoma of the lung. N. Engl. J. Med., 317: 1109–1113, 1987.
18.
BuckleyI.: Oncogenes and the nature of malignancy. Adv. Cancer Res., 50: 71–94, 1988.
19.
BunniG.R., EmanuelB.S., MeadowsA.T., BuckleyJ.D., WoodsW.G., HammondG.D.: Frequency of 13q abnormalities among 203 patients with retinoblastoma. J. Natl. Cancer Inst., 81: 370–374, 1989.
20.
CaseyG., SmithR., McGillivrayD., PetersG., DicksonC.: Characterization and chromosome assignments of the human homolog of int-2, a potential proto-oncogene. Mol. Cell. Biol., 6: 502–510, 1986.
21.
CaveneeW.K., DryjaT.P., PhillipsR.A., BenedictW.F., GodboutR., GallieB.L., MurphreeA.L., StrongL.C., WhiteR.L.: Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature, 305: 779–784, 1983.
22.
CiardielloE., KimN., LisciaD., BiancoC., LidereauR., MerloG., CallahanR., BrattainM., GreinerJ., SzpakC., KidwellW., DerynckR., SchlomJ., SalomonD.: Transforming growth factor alpha mRNA expression in human breast and colon carcinomas and TGF alpha activity in the effusions of cancer patients. J. Natl. Cancer Inst., in press., 1989.
23.
ClineM.J., BattiforaH., YokotaJ.: Proto-oncogene abnormalities in human breast cancer: correlation with anatomic features and clinical course of disease. J. Clin. Oncol., 5: 999–1005, 1987.
24.
CroceC.M.: Chromosome translocation and human cancer. Cancer Res., 46: 6019–6023, 1986.
25.
Delli BoviP., CuratolaA.M., KernF.G., GrecoA., IttmanM., BasilicoC.: An oncogene isolated by transfection of Kaposi's sarcoma DNA encodes a growth factor that is member of the FGF family. Cell, 50: 729–737, 1987.
26.
DevileeP., ThierryR.F., KievitsT., KolluriR., HopmanA.H.N., WillardH.F., PearsonP.L., CornelisseC.J.: Detection of chromosome aneuploidy in interphase nuclei from human primary breast tumors using chromosome-specific repetitive DNA probes. Cancer Res., 48: 5825–5830, 1988.
27.
De VitaV.T., HellmanS., RosenbergS.A.: Cancer principles and practice of oncology. Vol. 1, 2nd Ed., J.B. Lippincott, Philadelphia, pp. 31–66, 1985.
28.
DicksonC., PetersG.: Potential oncogene product related to growth factor. Nature, 326: 833, 1987.
29.
DrabkinH., KaoF.T., HartzJ., HartI., GazdarA., WeinbergerC., EvansR.: Localization of human erbA2 to the 3p22-3p24 region of chromosome 3 and variable deletion in small cell lung cancer. Proc. Natl. Acad. Sci. USA, 85: 9258–9262, 1988.
30.
DunnJ.M., PhillipsR.A., BeckerA.J., GallieB.: Identification of germline and somatic mutations affecting the retinoblastoma gene. Science, 241: 1797–1800, 1988.
31.
EscotC., TheilletC., LidereauR., SpyratosF., ChampemeM.H., GestJ., CallahanR.: Genetic alteration of the c-myc proto-oncogene in human primary breast carcinomas. Proc. Natl. Acad. Sci. USA, 83: 4834–4838, 1986.
32.
FearonE.R., FeinbergA.P., HamiltonS.H., VogelsteinB.: Loss of genes on the short arm of chromosome 11 in bladder cancer. Nature, 318: 377–380, 1985.
33.
Ferti-PassantonopoulouA.D., PananiA.D.: Common cytogenetic findings in primary breast cancer. Cancer Genet. Cytogenet., 27: 289–298, 1987.
34.
FriendS.H., DryjaT.P., WeinbergR.A.: Oncogenes and tumor suppressing genes. N. Eng. J. Med., 318: 618–622, 1988.
35.
FukushigeS.I., MastsubaraK.I., YoshidaM., SasakiM., SuzukiT., SembaK., ToyoshimaK., YamotoT.: Localization of a novel v-erbB related gene, c-erbB-2, on human chromosome 17 and its amplification in a gastric cancer cell line. Mol. Biol., 6: 955–958, 1986.
36.
GlaserT., LewisW.H., BrunsG.A.P., WatkinsP.C., RoglerC.E., ShowsT.B., PowersV.E., WillardH.F., GoguenJ.M., SimolaK.O.J., HousmanD.E.: The beta-subunit of follicle stimulating hormone is deleted in patients with aniridia and Wilms tumor, allowing a further definition of the WAGR locus. Nature, 321: 882–887, 1988.
37.
GreenA.R.: Recessive mechanisms of malignancies. Br. J. Cancer, 58: 115–121, 1988.
38.
HarbourJ.W., LaiS.L., Whang-PengJ., GazdarA., MinnaJ., KayeF.: Abnormalities in structure and expression of the human retinoblastoma gene in SCLC. Science, 241: 353–357, 1988.
39.
HorowitzJ.M., YandellD.W., ParkS.H., CanningS., WhiteP., BuchkovichK., HarlowE., WeinbergR.A., DryjaT.P.: Point mutational inactivation of the retinoblastoma antioncogene. Science, 243: 937–940, 1989.
40.
HuangH.J.S., YeeJ.K., ShewJ.Y., ChenP.L., BooksteinR., FriedmannT., LeeE.Y.P., LeeW.H.: Suppression of the neoplastic phenotype by replacement of the RB gene in human cancer cells. Science, 242: 1563–1566, 1988.
41.
KingC.R., KrausM.H., AaronsonS.A.: Amplification of a novel v-erbB-related gene in a human mammary carcinoma. Science, 229: 974–976, 1985.
42.
KleinG.: The approaching era of the tumor suppressor genes. Science, 238: 1539–1545, 1987.
43.
KovacsG., ErlandssonR., BoldogF., IngvarssonS., Muller-BrechlinR., KleinG., SumegiJ.: Consistent chromosome 3p deletion and loss of heterozygosity in renal cell carcinoma. Proc. Natl. Acad. Sci. USA, 85: 1571–1575, 1988.
44.
KozborD., CroceC.: Amplification of the c-myc oncogene in one of five human breast carcinoma cell lines. Cancer Res., 44: 438–441, 1984.
45.
KnudsonA.G.: Mutation and cancer: statistical study of retinoblastoma. Proc. Natl. Acad. Sci. USA, 68: 820–823, 1971.
46.
KnudsonA.G.: Hereditary cancer, oncogenes, and anti-oncogenes. Cancer Res., 45: 1437–1443, 1985.
47.
KrausM.H., PierceJ.H., FlemingT.P., RobbinsK.C., Di FioreP.P., AaronsonS.: Mechanism by which genes encoding growth factors and growth factor receptors contribute to malignant transformation. Ann. New York Acad. Sci., in press, 1989.
48.
KrausM.H., YuasaY., AaronsonS.A.: A position 12-activated H-ras oncogene in all HS578T mammary carcinosarcoma cells but not normal mammary cells of the same patient. Proc. Natl. Acad. Sci. USA, 81: 5384–5388, 1984.
49.
LeeW.H., BooksteinR., HongF., YoungL.J., ShewJ.Y., LeeE.Y.H.P.: Human retinoblastoma susceptibility gene: cloning, identification and sequence. Science, 235: 1394–13991987.
50.
LeeE.Y.H.P., ToH., ShewJ.Y., BrooksteinR., ScullyP., LeeW.H.: Inactivation of the retinoblastoma susceptibility gene in human breast cancers. Science, 241: 218–221, 1988.
51.
LidereauL., EscotC., TheilletC., ChampemeM.M., BrunetM., GestJ., CallahanR.: High frequency of rare alleles of the human c-Ha-ras-1 proto-oncogene in breast cancer patients. J. Natl. Cancer Inst., 77: 697–701, 1986.
52.
LidereauR., CallahanR., DicksonC., PetersG., EscotC., AliI.U.: Amplification of the int-2 gene in primary human breast tumors. Oncogene Res., 2: 285–291, 1988.
53.
LundbergC., SkoogL., CaveneeW.R., NordenskjoldM.: Loss of heterozygosity in human ductal breast tumors indicates a recessive mutation on chromosome 13. Proc. Natl. Acad. Sci. USA, 84: 2372–2376, 1987.
54.
LynchH.T., WatsonP., MarcusJ.N., CallahanR., SchlomJ., MerloG., ConwayT., FitzsimmonsM.L., LynchJ.: Hereditary breast cancer: a search for biomarkers. J. Tum. Marker One., 2: 153–159, 1987.
55.
McKayJ., SteelC.M., ElderP.A., ForrestA.P.M., EvansH.J.: Allele loss on short arm of chromosome 17 in breast cancers. Lancet, 2 (8625): 1384–1385, 1988.
56.
Mariani-CostantiniR., EscotC., TheilletC., GentileA., MerloG., LidereauR., CallahanR.: In situ c-myc expression and genomic status of the c-myc locus in infiltrating ductal carcinomas of the breast. Cancer Res., 48: 199–205, 1988.
57.
McGuireW.L.: Prognostic factors in primary breast cancer. Cancer Surv., 5: 527, 1986.
58.
MerloG., SiddiquiJ., CroppC., LisciaD., LidereauR., CallahanR., KufeD.: DF3 tumor-associated antigen gene is frequently altered in primary human breast carcinomas. Proc. Natl. Acad. Sci. USA, in press, 1989.
59.
ModjtahediN., LavielleC., PouponM.F., LaudinR.M., CassingenaR., MonierR., BrisonO.: Increased level of amplification of the c-myc oncogene in tumors induced in nude mice by a human breast carcinoma cell line. Cancer Res., 45: 4372–4379, 1985.
60.
MooreR., CaseyG., BrookesS., DixonM., PetersG., DicksonC.: Sequence, topography and protein coding potential of mouse int-2: a putative oncogene activated by mouse mammary tumor virus. EMBO J., 5: 919–924, 1986.
61.
MonpezatJ., DelattreO., BernardA., GrunwaldA., RemvikosY., MulerisM., SalmonR.J., FrelatG., DutrillauxB., ThomasG.: Loss of alleles on chromosome 18 and on the short arm of chromosome 17 in polyploid colorectal carcinomas. Int. J. Cancer, 41: 404–408, 1988.
62.
MorseB., RothbergP.G., SouthV.J., SpandorferJ.M., AstrinS.M.: Insertional mutagenesis of the myc locus by a LINE-1 sequence in a human breast carcinoma. Nature, 333: 87–90, 1988.
63.
MullerW.J., SinnE., PattengaleP.K., WallaceR., LederP.: Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell, 54: 105–115, 1988.
64.
National Cancer Institute, 1987 Annual Cancer Statistics Review NIH Publication No. 88: 2789, 1987.
65.
NaylorS.L., JohnsonB.E., MinnaJ.D., SakaguchiA.Y.: Loss of heterozygosity of chromosome 3p markers in small-cell lung cancer. Nature, 329: 451–454, 1987.
66.
NowellP.C.: Molecular events in tumor development. N. Engl. J. Med., 319: 575–576, 1988.
67.
PetrakisN.L.: Genetic factors in the etiology of breast cancer.39: 2709–2715, 1977.
68.
PonderB.: Gene losses in human tumors. Nature, 335: 400–402, 1988.
69.
RabbitsP.H., DouglasJ., FischerP., NachevaE., KarpasA., CatovskyD., MeloJ.V., BaerR., StinsonM.A., RabbitsT.H.: Chromosome abnormalities at llql3 in B cell tumors. Oncogene, 3: 99–103, 1988.
70.
RiderS.H., GormannP.A., ShipleyJ.M., MooreG., VennstromB., SolomonE., SheerD.: Localization of the oncogene c-erbA2 to human chromosome 3. Ann. Hum. Genet., 51: 153, 1987.
71.
RodgerC.S., HillS.M., HultenM.A.: Cytogenetic analysis in human breast carcinoma. I. Nine cases in the diploid range investigated using direct preparations. Cancer Genet. Cytogenet., 13: 95–119, 1984.
72.
SakamotoH., MoriM., TainaM., YoshidaT., MatsukawaS., ShimizuK., SekuguchiM., TeradaM., SugimuraT.: Transforming gene from human stomach cancers and a non cancerous portion of stomach mucosa. Proc. Natl. Acad. Sci. USA, 83: 3997–3901, 1986.
SchwartzA.G., KingM.H., BelleS.H., SatarianoW.H., SwansonG.M.: Risk of breast cancer to relatives of young breast cancer patients. J. Natl. Cancer Inst., 75: 665–668, 1985.
75.
SeinzingerB.R., RouleauG.A., OzeliusL.J., LaneA.H., FarmerG.E., LamiellJ.M., HainesJ., YuenJ.W.M., CollinsD., Majoor-KrakauerD., BonnerT., MathewC., RubensteinA., HalperinJ., McConkie-RosellA., GreenJ.S., TrofatterJ.A., PonderB.A., EiermanL., BowmerM.I., SchimkeR., OostraB., AroninN., SmithD.I., DrabkinH., WaziriM.H., HobbsW.J., MartuzaR.L., ConneallyP.M., HsiaY.E., GusellaJ.F.: Von Hippel-Lindau disease maps to the region of chromosome 3 associate with renal cell carcinoma. Nature, 332: 268–269, 1988.
76.
ShihC., PadhyL., MurrayM., WeinbergR.A.: Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts. Nature, 290: 261–264, 1981.
77.
SiddiquiJ., AbeM., HayesD., ShaniE., YunisE., KufeD.: Isolation and sequencing of cDNA coding for the human DF3 breast carcinoma-associated antigen. Proc. Natl. Acad. Sci. USA, 85: 2320–2323, 1988.
78.
SinnE., MullerW., PattengaleP., TeplerI., WallaceR., LederP.: Coexpression of MMTV/v-Ha-ras and MMTV/ c-myc genes in transgenic mice: synergistic actions of oncogenes in vivo. Cell, 49: 465–475, 1987.
79.
SlamonD.J., ClarkG.M., WongS.G., LevinW.J., UllrichA., McGuireW.L.: Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science, 235: 177–181, 1987.
80.
StenmanG., SagerR.: Genetic analysis of tumorigenesis: a conserved region in the human and chinese hamster genomes contains genetically identified tumor-suppressor genes. Proc. Natl. Acad. Sci. USA, 84: 9099–9102, 1987.
81.
StewartT., PattengaleP., LederP.: Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MMTV/myc fusion genes. Cell, 38: 627–637, 1984.
82.
StolerA., BouckN.: Identification of a single chromosome in the normal human genome essential for suppression of hamster cell transformation. Proc. Natl. Acad. Sci. USA, 82: 570–574, 1985.
83.
SwallowD., GendlerS., GriffithsB., KearneyA., PoveyS., SheerD., PalmerR.W., Taylor-PapadimitriouJ.: The hypervariable gene locus PUM, which codes for the tumor associated epithelial mucins, is located on chromosome 1, within the region lq21-24. Ann. Hum. Genet., 51: 289–294, 1987.
84.
T'andA., VarleyJ.M., ChakrabortyS., Linn MurphreeA., FungY.K.T.: Structural rearrangement of the retinoblastoma gene in human breast carcinoma. Science, 242: 263–266, 1988.
85.
TheilletC., LidereauR., EscotC., HutzellP., BrunetM., GestJ., SchlomJ., CallahanR.: Frequent loss of a H-ras-1 allele correlates with aggressive human primary breast carcinomas. Cancer Res., 46: 4776–4781, 1987.
86.
TrentJ.M.: Cytogenetic and molecular biology alterations in human breast cancer: a review. Breast Cancer Res. Treat., 5: 221–229, 1985.
87.
TsujimotoY., JaffeE., CossmanJ., GorhamJ., NowellP.C., CroceC.M.: Clustering of breakpoints on chromosome 11 in human B-cell neoplasms with the t(11;14) chromosomal translocation. Nature, 315: 340–343, 1985.
88.
TsutsumiM., YokotaJ., KakizoeT., KoisoK., SugimuraT., TeradaM.: Loss of heterozygosity on chromosome 1p and 11p in sporadic pheochromocytoma. J. Natl. Cancer Inst., 81: 367–370, 1989.
89.
Van de VijverM., Van de BersselaarR., DevileeP., CornelisseC., PeterseJ., NusseR.: Amplification of neu (c-erbB2) oncogene in human mammary tumors is relatively frequent and is often accompanied by amplification of the linked c-erbA oncogene. Mol. Cell. Biol., 7: 2019–2023, 1987.
90.
VarleyJ.M., SwallowJ.E., BrammarW.J., WhittakerJ.L., WalkerR.A.: Alteration to either c-erbB2 or c-myc proto-oncogenes in breast carcinomas correlate with poor short-term prognosis. Oncogene, 1: 423–430, 1987.
91.
VarmusH.E.: The molecular genetics of cellular oncogenes. Ann. Rev. Genet., 18: 553–612, 1984.
92.
VogelsteinB., FearonE.R., HamiltonS.R., KernS.E., PreisingerA.C., LeppertM., NakamuraY., WhiteR., SmitsA.M.M., BosJ.L.: Genetic alterations during colorectal tumor development. N. Engl. J. Med., 319: 525–532, 1988.
93.
WeinbergerC., ThompsonC.C., OngE.S., LeboR., GruolD.J., EvansR.M.: The erbA gene encodes a thyroid hormone receptor. Nature, 324: 641–646, 1986.
94.
WeissR.A., TeichN., VarmusH., CoffinJ.: Molecular biology of tumor viruses. 2nd Ed. Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.1984.
95.
WhittakerY., WalkerR., VarleyY.: Differential expression of cellular oncogenes in benign and malignant human breast tissue. Int. J. Cancer, 38: 651–655, 1986.
96.
YokotaJ., YamamotoT., ToyoshimaK., TeradaM., SugimuraT., BattiforaH., ClineH.J.: Amplification of c-erb-B2 oncogene in human adenocarcinomas in vivo. Lancet, 1: 765–767, 1986.
97.
YokotaJ., WadaM., ShimosatoY., TeradaM., SugimuraT.: Loss of heterozygosity on chromosome 3, 13 and 17 in small cell carcinoma and on chromosome 3 in adenocarcinoma of the lung. Proc. Natl. Acad. Sci. USA, 84: 9252–9256, 1987.
98.
YoshidaT., MiyagawaK., OdagiriH., SakamotoH., LittleP.F., TeradaM., SugimuraT.: Genomic sequence of hst, a transforming gene encoding a protein homologous to fibroblast growth factors and the int-2 encoded protein. Proc. Natl. Acad. Sci. USA, 84: 7305–7309, 1987.
99.
ZarblM., SukumarS., ArthurA., ZancaD., BarbacidM.: Direct mutagenesis of Ha-ras-l oncogenes by N-nitroso-N-methyl urea during initiation of mammary carcinogenesis in rats. Nature, 315: 382–385, 1985.
100.
ZbarB., BrauchH., TalmadgeL., LiuehanM.: Loss of alleles of loci on the short arm of chromosome 3 in renal cell carcinoma. Nature, 327: 721–724, 1987.
101.
ZhouD., BattiforaH., YokotaJ., YamamotoT., ClineM.J.: Association of multiple copies of the c-erbB2 oncogene with spread of breast cancer. Cancer Res., 47: 6123–6125, 1987.
102.
ZhouD.J., CaseyG., ClineM.J.: Amplification of human int-2 in breast cancers and squamous carcinomas. Oncogene, 2: 279–282, 1988.
