IN PERSPECTIVEClaudio J. Conti, Editor

Breast Cancer: Genetic Predisposition andExposure to Radiation

L. Michelle Bennett*

Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park,North Carolina

The identification of breast cancer susceptibility genes, such as BRCA1, BRCA2, ATM, and p53, has beenaccompanied by the examination of the effects of radiation in combination with genetic mutations at these loci.Women at high risk for developing breast cancer may respond differently than the general population to low- andhigh-dose radiation exposures associated with screening and treatment. Epidemiologic studies are being performed toinvestigate the effects of radiation on subsequent breast cancer development in genetically predisposed individuals.Mouse strains with specific genetic modifications are being created to study the consequence of both inheritedmutations and radiation on mammary gland carcinogenesis. Finally, studies investigating DNA damage±responsepathways after radiation exposure are being performed. Recent work on the effects of several known or suspectedbreast cancer susceptibility genes, alone or in combination with radiation, is presented here, and directions for futureresearch are considered. Mol. Carcinog. 26:143±149, 1999. # 1999 Wiley-Liss, Inc.

Key words: breast cancer; (genetic) susceptibility; radiation; BRCA1; BRCA2

INTRODUCTION

Of the 180 000 cases of breast cancer diagnosed inthe United States this year, approximately 7±10%can be attributed to genetic inheritance. Severalgenes are known to predispose women to breastcancer, including BRCA1, BRCA2, p53, the ataxiatelangiectasia (AT) gene (ATM), and adenomatouspolyposis coli (APC). Individual responses to radia-tion exposure resulting from breast cancer screeningor treatment protocols are probably governed byvarious susceptibility and modi®er loci. The identi-®cation and understanding of such susceptibilitygenes may have positive rami®cations in the clinicalsetting by enhancing the ability to predict indivi-dual radiation responses or to customize radio-therapy treatments.

Numerous studies have shown that radiation is ahuman breast carcinogen and has the potential toboth initiate and promote the neoplastic process.Epidemiologic studies of women who were atomicbomb survivors or were treated with radiation formedical conditions, such as Hodgkin's disease,demonstrated that exposure to ionizing radiationis associated with an increased risk for breast cancerdevelopment [reviewed in 1]. Radiation has manybiological effects, including cell-cycle arrest orprogrammed cell death [2,3]; chromosomal break-age, which can lead to gene ampli®cation, deletion,and/or rearrangement [4,5]; alterations in geneexpression [2,6,7]; and changes in microenviron-ment that may be conducive to initiation orpromotion [7]. While radiation is commonly usedfor screening and is a valuable therapeutic optionfor many cancers, the potential for negative long-

term outcomes exist. The challenge is to ef®cientlyuse ionizing radiation to screen and treat cancerpatients while minimizing their risk of developingrecurrences or second primary cancers. Results fromCanadian ¯uoroscopy patients and Japanese atomicbomb survivors suggested that the relative risk forbreast cancer development, beginning 5±10 yr afterexposure, remains constant for at least severaldecades [8]. It is important to consider the possibi-lity that genetically predisposed populations mayhave an increased sensitivity to environmentalexposures such as radiation. Addressing the ques-tion of gene-environment interactions is particu-larly important in populations of women who haveinherited mutations in genes that play a role inDNA-damage response, cell-cycle control, or tumorsuppression.

Currently, little is known about radiation riskfactors in women who are genetically predisposed tobreast cancer development. Several approaches arebeing used to understand these radiation-geneinteractions, including epidemiologic studies, theuse and development of animal models, andmechanistic studies in vitro. These investigationsmay lead to the identi®cation of human loci thatpredispose or protect individuals from radiation-induced breast cancer and facilitate subsequent

MOLECULAR CARCINOGENESIS 26:143±149 (1999)

# 1999 WILEY-LISS, INC.

*Correspondence to: Laboratory of Molecular Carcinogenesis,National Institute of Environmental Health Sciences, 111 T.W.Alexander Drive, Research Triangle Park, NC 27709.

Received 12 April 1999; Revised 23 June 1999; Accepted 29 June1999

Abbreviations: AT, ataxia telangiectasia; APC, adenomatouspolyposis coli.

strategies for cancer detection and treatment basedon genetics.

BREAST CANCER SUSCEPTIBILITY GENESAND RADIATION

Women who inherit a mutation in either theBRCA1 or BRCA2 gene are predisposed to thedevelopment of breast cancer at an early age. Therisks of BRCA1 and BRCA2 mutation carriers devel-oping breast cancer by 50 yr of age are 49% and 28%,respectively [9,10]. The lifetime risk for breast cancerdevelopment in these women has been determinedto be as high as 85%. While the functions of theBRCA1 and BRCA2 gene products have yet to beelucidated, it has been established that they bothinteract with the RAD51 protein [11±13] and maybe involved in meiotic and mitotic recombinationas well as multiple DNA damage±repair pathways[11,14±16]. Women who are at high risk fordeveloping breast cancer, such as women fromfamilies known or suspected of harboring BRCA1or BRCA2 mutations, are receiving recommenda-tions to begin having semiannual mammograms at25 yr of age [17]. In contrast, women in the generalpopulation are encouraged to begin annual orbiannual breast cancer screening between the agesof 40 and 50. A typical mammographic sessionincludes two views for each breast and a totalradiation exposure of approximately 3 mGy perbreast [18,19]. Thus, the potential lifetime radia-tion exposures from mammography of women athigh risk for breast cancer development are sig-ni®cantly greater than those of women in thegeneral population.

While the age at which to begin mammographicscreening in the general population is controversial[20,21], epidemiologic studies have shown that thebene®ts of mammography outweigh the risks ofradiation exposure [18]. Such epidemiologic studiesneed to be performed for women at high risk fordeveloping breast cancer, such as women whoinherit alterations in the BRCA1 or BRCA2 genes.While epidemiologic studies are needed, a mathe-matical model for cancer predisposition and radio-sensitivity has been developed and was used tomake predictions about BRCA1 mutation carriers[22]. Published information regarding both BRCA1and radiation exposure from human and animalstudies, was applied to this autosomal dominantmodel. The results from the model led the authorsto predict that the bene®ts of mammography willoutweigh the risks of radiation in the BRCA1-predisposed population. Carefully designed epide-miologic studies will need to be performed todetermine if this prediction is correct.

Women who have inherited a BRCA1 or BRCA2mutation may be at increased risk for radiation-induced DNA damage. Breast tumor development inBRCA1 and BRCA2 mutation carriers is associated

with the inactivation of the wild-type allele and hasled to the classi®cation of these genes as tumorsuppressors [23]. Breast tumors that have inacti-vated both BRCA1 or BRCA2 alleles may be moresusceptible to radiation because their BRCA1 andBRCA2 protein products, which appear to beinvolved in radiation-induced DNA damage±repairpathways, are compromised [24]. Thus, these tumorcells may not be able to make the necessary repairsfor continued growth and would subsequently beeliminated by radiotherapy.

CONSERVATIVE SURGERY AND RADIATIONTHERAPY IN WOMEN WITH FAMILY HISTORIES

OF BREAST CANCER

Conservative surgery followed by radiotherapy isone approach for managing breast cancer. Thistreatment involves surgical removal of the tumorfrom the breast followed by total therapeuticradiation doses of approximately 50±60 Gy over aseveral-week period to kill any remaining cancercells [25]. During such treatment, the contralateralbreast will receive doses in the 0.5±6 Gy range [25±27], a range in which the dose-response curve forradiation exposure and breast cancer developmenthas been suggested to be linear [25]. Conservativesurgery with radiotherapy might be an attractivetreatment strategy for many highly predisposedbreast cancer patients whose tumors may haveinactivated both BRCA1 or BRCA2 alleles. However,this therapeutic approach will result in radiationexposure of surrounding normal tissues that areheterozygous for BRCA1 or BRCA2 mutation andmay induce mutations that could contribute tosubsequent cancer development in later years.

The consequences of breast-conserving surgeryand radiotherapy have been considered for womenin the general population. A study by Boiceet al. [26] demonstrated an approximately 11%increased risk for breast cancer development inthe contralateral breast for women treated withconservation surgery and radiotherapy at age 45 oryounger. In addition, women who have conserva-tion surgery and radiotherapy earlier in life aremore susceptible to radiation-induced breastcancer, as evidenced by their rates of recurrence,which are higher than those observed in olderwomen [28,29]. In general, BRCA1 and BRCA2mutation carriers develop breast cancer at signi®-cantly younger ages than do women in the generalpopulation. Therefore, determination of whetheryounger, high-risk patients harbor BRCA1 or BRCA2mutations might enable clinicians to select the mostappropriate treatment strategies for this predisposedgroup.

Several investigations have recently examined theeffects of breast-conservation and radiation therapyin women with positive family histories of breastcancer [28±32]. Haas et al. [28] designed a study to

144 BENNETT

determine if women with a family history of breastcancer are more susceptible to ipsilateral breastcancer after treatment than are women without afamily history of disease. The patients were nottested for mutations in the BRCA1 and BRCA2genes, but it was suggested that those womendiagnosed with cancer at an early age were morelikely to carry a germline mutation than womendiagnosed later in life. In this study, breast-con-servation therapy and radiation treatment did notincrease the risk for ipsilateral breast cancer inwomen with family histories of breast cancercompared with the control group during a 5-yrfollow-up period. Mutation screening in thepatients in this study would have provided concreteinformation about BRCA1 and BRCA2 germlinedefects in combination with high-dose radiation.

Several recent reports focused on breast cancerpatients with known BRCA1 or BRCA2 mutationsafter breast conservation treatment and radiationtherapy [30±32]. No difference in local recurrencewas observed, up to 5 or 10 yr after treatment,between BRCA mutation carriers and age-matchedcontrols who were diagnosed with sporadic breastcancer [30±32]. The continued study and follow-upof these women will be critical for estimating thelong-term breast cancer risk in the contralateralbreasts of predisposed women. Given both thepotentially long time between radiation exposureand cancer development and the early age of breastcancer onset for many predisposed women, theresults from long-term studies investigating con-servation surgery and radiotherapy effects inwomen at high risk for breast cancer will be valuablefor a more complete understanding of at least somegene-radiation interactions.

The development of animal models is anotherapproach for investigating the interactions betweenthe BRCA genes and radiation. A recent studycompared mammary tumor induction in Brca1�/�

and Brca1�/ÿ mice on a p53�/ÿ background inresponse to high-dose radiation (5 Gy) [33]. Fivemammary tumors were observed in Brca1�/ÿ/p53�/ÿ

mice, whereas none were seen in the Brca1�/�/p53�/ÿ

group. While these results failed to achieve statis-tical signi®cance, they may be biologically impor-tant. Molecular analysis con®rmed that all of themammary tumors showed loss of heterozygosity ofp53 and that three of the ®ve had lost the wild-typeBrca1 allele. However, the authors could not rule outthat large-scale losses of heterozygosity includingBrca1 explained the loss of gene expression. Themouse Brca1 and p53 genes are both located onchromosome 11 [34,35].

The study of Brca1 and Brca2 gene±de®cient micewith different inbred genetic backgrounds, aloneand in combination with other breast cancersusceptibility or modi®er genes, may provide infor-mation about the effects of gene-gene interactions

on mammary tumor induction and susceptibility toradiation exposure. To date, almost all Brca1- andBrca2-homozygous mutant mice have died in utero.The few homozygous mutant mice that havesurvived, succumbed to thymic lymphoma at anearly age [reviewed in 36]. Current strategies fordeveloping Brca mouse models focus largely on thedevelopment of conditional knockouts. Recently,inactivation of the Brca1 gene in the mousemammary gland was achieved by using the Cre/LoxP system and subsequently led to tissue-speci®ctumor development [37]. These mice may be apowerful model in which to study exposure toionizing radiation.

AT AND RADIATION EXPOSURE

AT is an inherited autosomal recessive diseasecharacterized by cerebellar degeneration, dilatedblood vessels in the eye, immune de®ciencies,degeneration of the thymus, and sensitivity toionizing radiation [38]. Individuals heterozygousfor a mutated copy of the AT gene (ATM) are alsosensitive to ionizing radiation [38]. ATM hetero-zygotes are at an increased risk for breast cancerdevelopment that is most apparent in older patients[39,40]. In addition, Swift and coworkers, [41]reported that exposure to ionizing radiationincreases that risk. Studies designed to test thehypothesis that approximately 8% of breast cancerin patients diagnosed before age 40 occurs in ATheterozygotes [42,43] failed to demonstrate a clearassociation between ATM and early-onset breastcancer [44,45]. Young women heterozygous for ATmutations may be at an increased risk for breastcancer development. The need for studies examin-ing the effects of radiation exposure from mammo-graphy, diagnostic radiology, and radiationtreatments of AT heterozygotes has been recognized[46,47]. A small study was conducted in which ATmutation status was determined in a limitednumber of breast cancer patients who had severelate reactions to radiotherapy and whose cellsdemonstrated radiosensitivity in vitro [48]. Theauthors concluded that testing for AT mutationswould not help predict response to radiationtherapy. Approximately 1% of the populationcarries a mutation at the AT locus yet shows nooutward symptoms of disease. Interestingly, anexon-24 ATM sequence variant has been describedthat is associated with an increased risk for breastcancer development [49]. The risk is furtherincreased when the individual also harbors a rareHa-ras-1 allele [49]. How AT mutations or poly-morphisms might interact with alterations in theBRCA or p53 genes in humans is not known.

Atmÿ/ÿ mice have been developed, have a pheno-type similar to that of human AT patients, and arehighly sensitive to radiation exposure [50,51].Radiation treatment of wild-type, Atm�/ÿ, and

BREAST CANCER: GENETICS AND RADIATION 145

Atmÿ/ÿ mice with 4 Gy results in the death of two-thirds of the Atmÿ/ÿ mice, whereas animals in theother groups survive to at least 2 mo of age [50]. Arecent study demonstrated that some compart-ments of the developing central nervous systemsof Atmÿ/ÿ mice are resistant to radiation-inducedapoptosis [52]. Westphal et al. [53] reported thatinhibiting Atm function in p53ÿ/ÿ cells rendersmultiple tissues sensitive to ionizing radiation [53].Barlow et al. [54] have shown that the treatment ofAtm�/� and Atm�/ÿ mice with 4 Gy between 2 and4 mo of age signi®cantly reduces the average life-span of the heterozygous mice from 93 to 73 wk.One mammary tumor was observed in one of theAtm�/ÿ mice but not in any Atm�/� mice, and nosigni®cant differences in tumor development atother sites were observed between these mice. Theauthors stated that the relevance of these studies tohuman AT carriers is not clear. However, they dosuggest, by extrapolation of their data to humans,that AT carriers may be sensitive to high sublethaldoses of radiation.

GENE-GENE INTERACTIONS

APC is a tumor suppressor gene that whenmutated is involved in sporadic and inherited coloncancer and predisposes individuals to the develop-ment of hundreds to thousands of colorectal polyps,a subset of which can acquire the ability to progressto carcinomas [55,56]. Recent studies have investi-gated the association between the I1307K APCallele, which is found in approximately 7% of theAshkenazi population, and the development ofbreast cancer [57,58]. The I1307K polymorphismgives rise to an unstable An sequence in the APCcoding region that enhances the possibility ofpolymerase slippage during DNA replication. Breastcancer patients who inherit the I1307K allele aretwice as likely to carry a mutation in one of thebreast cancer susceptibility genes, BRCA1 or BRCA2,than are controls. Thus, it has been suggested thatthe APC gene may be a low-penetrance breast cancersusceptibility gene or perhaps a modi®er of theBRCA loci [56,57].

There are several Apc mutant mouse strains thatare predisposed to spontaneous intestinal tumors[59,60] similar to those observed in humans withinherited APC mutations. The ApcMin mutant micewere identi®ed by Moser and coworkers [61] asbeing highly susceptible to the development ofmultiple intestinal neoplasias. In addition to devel-oping intestinal tumors, the ApcMin mice are suscep-tible to mammary tumor induction when treatedwith the alkylating agent N-ethyl-N-nitrosourea[62]. In another study, investigators used Apc1638Nmutant mice to study the effects of radiationexposure on intestinal tumors [63]. FemaleApc1638N mice were irradiated at 7 wk of age witha dose of 5 Gy. In addition to ®nding an increase in

intestinal tumors after irradiation, the authorsobserved a 15-fold increase in mammary tumorincidence in these animals. Thus, the mutant Apcgenotype can confer high susceptibility to bothchemically induced and radiation-induced mam-mary tumorigenesis. The human APC gene may playa role in sensitivity to breast cancer development bymodulating the effect of other breast cancer suscept-ibility genes. Thus, it is prudent to considerpotential interactions between this gene and radia-tion exposure.

GENETIC SUSCEPTIBILITY TO RADIATION-INDUCEDMAMMARY CARCINOGENESIS IN MICE

One of the many barriers to understanding theeffects of environmental exposure on mouse modelsis the variation in the genetic backgrounds onwhich the gene of interest is studied. To investigatepotential gene-gene interactions in combinationwith radiation or other exposures, mice can be bredto produce several genotypic combinations of thegenes of interest. In so doing, mouse strains areoften created that have unique genetic constitu-tions regarding the altered genes as well as thegenetic background.

To understand better the contribution of geneticbackground to radiation-induced mammary tumorsusceptibility, Ullrich and coworkers [64] used theC57BL/6 and BALB/c mouse strains, which arerelatively resistant and sensitive, respectively [64].Using these inbred mouse strains, Ullrich's groupmade several important observations. First, theradiation-sensitive compartment of the mammarygland appears to be the epithelial cells [65]. Usingthe mammary fat pad clearance and transplantationtechnique ®rst described by DeOme [66], Ullrichand colleagues showed that the introduction ofirradiated epithelial cells from BALB/c mice into thefat pads on the resistant (BALB/c�C57BL/6)F1 micefrequently resulted in the development of ductaldysplasias. This was also observed when the epithe-lial cells were transplanted into susceptible BALB/crecipients. When the reciprocal experiment wasperformed (that is, transplantation of irradiatedmammary epithelial cells from (BALB/c�C57BL/6)F1 mice into sensitive BALB/c mice), ductaldysplasias did not develop. Thus, C57BL/6 epithelialcells appear to express a dominant suppressor thatinhibits ductal dysplasia in F1 epithelial cells. Inaddition, the incidence of ductal dysplasia corre-lates strongly with mammary tumor formation inthese mouse strains [65].

Ponnaiya et al. [67] have observed a difference inthe ability of C57BL/6 and BALB/c mammaryepithelial cells to recover from radiation-inducedDNA damage. In these experiments, primary epithe-lial cell cultures were established from the mam-mary glands of the two strains and treated with atotal dose of 3 Gy. The delayed appearance of

146 BENNETT

radiation-induced chromosomal aberrations, a mea-sure of DNA damage, persisted in the BALB/c mousecells to 28 population doublings. In contrast, afteronly six population doublings, the aberrations inthe C57BL/6 cells returned to control levels. Thus,the epithelial cells from BALB/c mice demonstrateincreased instability resulting from the radiationexposure as compared with cells from C57BL/6mammary glands.

The extremes in sensitivity among inbred mousestrains may be useful for identifying radiation-sensitivity loci in mice which may facilitate sub-sequent identi®cation of human orthologues. Twoinbred mouse strains that differ greatly in suscep-tibility, such as C57BL/6 and BALB/c, could be usedto map the main genes that govern the radiation-sensitive phenotype. It is also possible that modi®ergenes that in¯uence mammary tumorigenesis byincreasing or decreasing sensitivity can be localized.Quantitative trait loci responsible for radiation-induced pulmonary ®brosis in a C3H/He�C57BL/6backcross were identi®ed by selecting inbred mousestrains that differed in their responses [68]. Havingmapped the mouse loci, the authors hope toextend their ®ndings to the human population toidentify the human orthologues. In this way,individuals who are genetically predisposed to thedevelopment of lung damage could be identi®edand radiation treatments customized based onthat information.

CONCLUSION

Investigators will continue to discover genes thatmodify breast cancer risks. Dissecting the complexinterplay among genetic factors and radiationexposure by examining human populations andmouse models will undoubtedly be very challen-ging. The contribution of information from epide-miologic studies will be essential for furthering ourunderstanding of the interaction of low- and high-dose radiation exposure and genetic susceptibility.Epidemiologic studies carefully designed to testwhether radiation exposure poses an additional riskfor breast cancer in predisposed individuals will takemany years of study and follow-up. In the mean-time, the generation and use of mice with targetedgenetic alterations in addition to in vitro studies willprovide complementary information about gene-radiation interactions. This multidisciplinaryapproach could lead to mechanism-based recom-mendations for screening, diagnosis and treatmentinvolving radiation exposure for younger womenpredisposed to breast cancer development. If thereare populations that have an increased sensitivity toradiation-induced breast cancer development, itwould be highly desirable to identify those womenso that appropriate strategies can be used to reducetheir possibility of cancer development and recur-rence.

ACKNOWLEDGMENTS

I thank Roger Wiseman, Barbara Davis, KimberlyMcAllister, and Keith Collins for critical review ofthe manuscript and for helpful suggestions. I amsupported by United States Army Medical Researchand Materiel Command Grant DAMD 17-97-1-7027.

REFERENCES

1. Goss PE, Sierra S. Current perspectives on radiation-inducedbreast cancer. J Clin Oncol 1998;16:338±347.

2. Crompton NEA. Programmed cellular response in radiationoncology. Acta Oncol 1998;37 (Suppl 11):1±49.

3. Lane D. Awakening angels. Nature 1998;394:616±617.4. Storer JB. Acute responses to ionizing radiation. In: Earl L.

Green, editor. Biology of the laboratory mouse. New York:Dover; 1972. p 427.

5. Hutchinson F. Molecular biology of mutagenesis of mam-malian cells by ionizing radiation. Semin Cancer Biol1998;4:85±92.

6. Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, CraigRW. Participation of p53 protein in the cellular response toDNA damage. Cancer Res 1991;51:6304±6311.

7. Barcellos-Hoff MH. The potential in¯uence of radiation-induced microenvironments in neoplastic progression.Journal of Mammary Gland Biology and Neoplasia1998;3:165±175.

8. Howe GR, McLaughlin J. Breast cancer mortality between1950 and 1987 after exposure to fractionated moderate-dose-rate ionizing radiation in the Canadian FluoroscopyCohort Study and a comparison with breast cancer mortalityin the Atomic Bomb Survivors Study. Radiat Res 1996;145:694±707.

9. Ford D, Easton DF, Stratton M, et al. Genetic hetero-geneity and penetrance analysis of the BRCA1 and BRCA2genes in breast cancer families. Am J Hum Genet 1998;62:676±689.

10. Rahman N, Stratton M. The genetics of breast cancersusceptibility. Annu Rev Genet 1998;32:95±121.

11. Scully R, Chen J, Plug A, et al. Association of BRCA1with Rad51 in mitotic and meiotic cells. Cell 1997;88:265±275.

12. Sharan SK, Morimatsu M, Albrecht U, et al. Embryoniclethality and radiation hypersensitivity mediated by Rad51 inmice lacking Brca2. Nature 1997;386:804±810.

13. Chen P-L, Chen C-F, Chen Y, Xiao J, Sharp ZD, Lee W-H. TheBRC repeats in BRCA2 are critical for RAD51 binding andresistance to methyl methanesulfonate treatment. Proc NatlAcad Sci USA 1998;95:5287±5292.

14. Patel KJ, Yu VPC, Lee HS, et al. Involvement of Brca2 in DNArepair. Molecular Cell 1998;1:347±357.

15. Gowen LC, Avrutskaya AV, Latour AM, Koller BH, LeadonSA. BRCA1 required for transcription-coupled repair ofoxidative DNA damage. Science 1998;281:1009±1012.

16. Chen J-J, Sliver D, Cantor S, Livingston DM, Scully R.BRCA1, BRCA2, and Rad51 operate in a common DNAdamage response pathway. Cancer Res 1999;59:1752s±1756s.

17. Burke W, Daly M, Garber J, et al. Recommendationsfor follow-up care of individuals with an inheritedpredisposition to cancer. II. BRCA1 and BRCA2.Cancer Genetics Studies Consortium. JAMA 1997;26:997±1003.

18. Mettler FA, Upton AC, Kelsey CA, Ashby RN, Rosenberg RD,Linver MN. Bene®ts versus risks from mammography.Cancer 1996;77:903±909.

19. Suleiman OH, Spelic DC, McCrohan JL, Symonds GR, HounF. Mammography in the 1990's: The United States andCanada. Radiology 1999;210:345±351.

20. Taubes G. The breast screening brawl. Science 1997;275:1056±1059.

BREAST CANCER: GENETICS AND RADIATION 147

21. Fletcher SW. Whither scienti®c deliberation in healthpolicy recommendations? N Engl J Med 1997;336:1180±1183.

22. Chakraborty R, Sankaranarayanan K. Mutations in theBRCA1 gene: Implications of inter-population differencesfor predicting the risk of radiation-induced breast cancers.Genet Res 1998;72:191±198.

23. Bertwistle D, Ashworth A. Functions of the BRCA1 andBRCA2 genes. Curr Opin Genet Dev 1998;8:14±20.

24. Briggs PJ, Bradley A. A step toward genotype-basedtherapeutic regimens for breast cancer in patients withBRCA2 mutations? J Natl Cancer Inst 1998;90:951±953.

25. Harris JR, Recht A. Conservative surgery and radiotherapy.In: Harris JA, editor. Breast diseases. Philadelphia: Lippin-cott, 1991. p 388±419.

26. Boice JD, Harvey EB, Blettner M, Stovall M, Flannery JT.Cancer in the contralateral breast after radiotherapy forbreast cancer. N Engl J Med 1992;326:781±785.

27. Frass BA, Robertson PL, Lichter AS. Dose to the contralateralbreast due to primary breast irradiation. Int J Radiat OncolBiol Phys 1985;11:485±497.

28. Hass JA, Schultz DJ, Peterson ME, Solin LJ. An analysis of ageand family history on outcome after breast-conservationtreatment: The University of Pennsylvania experience.Cancer J Sci Am 1998;4:308±315.

29. Harrold EV, Turner BC, Matloff ET, et al. Local recurrence inthe conservatively treated breast cancer patient: A correla-tion with age and family history. Cancer J Sci Am1998;4:302±307.

30. Robson M, Gilewski T, Haas B, et al. BRCA-associated breastcancer in young women. J Clin Oncol 1998;16:1642±1649.

31. Verhoog LC, Brekelmans CTM, Seynaeve C, et al. Survivaland tumor characteristics of breast-cancer patients withgermline mutations of BRCA1. Lancet 1998;351:316±321.

32. Gaffney DK, Brohet RM, Lewis CM, et al. Response toradiation therapy and prognosis in breast cancer patientswith BRCA1 and BRCA2 mutations. Radiother Oncol 1998;47:129±136.

33. Cressman VL, Backlulnd DC, Hicks EM, Gowen LC, GodfreyV, Koller BH. Mammary tumor formation in p53- andBRCA1-de®cient mice. Cell Growth Differ 1999;10:1±10.

34. Lossie AC, MacPhee M, Burchberg AM, Camper SA. Mousechromosome 11. Mamm Genome 1994;5:S164±S180.

35. Bennett LM, Haugen-Strano A, Cochran C, Brownlee HA,Fiedorek FT Jr, Wiseman RW. Isolation of the mousehomologue of BRCA1 and genetic mapping to mousechromosome 11. Genomics 1995;29:576±581.

36. Hakem R, de la Pompa JL, Mak TW. Developmental studiesof Brca1 and Brca2 knock-out mice. Journal of MammaryGland Biology and Neoplasia 1998;3:431±445.

37. Xu X, Wagner K-U, Larson D, et al. Conditional mutation ofBrca1 in mammary epithelial cells results in blunted ductalmorphogenesis and tumor formation. Nat Genet 1999;22:37±43.

38. Savitsky K, Bar-Shira A, Gilad S, et al. A single ataxiatelangiectasia gene with a product similar to PI-3 kinase.Science 1995;268:1749±1753.

39. Athma P, Rappaport R, Swift M. Molecular genotypingshows that ataxia-telangiectasia heterozygotes are predis-posed to breast cancer. Cancer Genet Cytogenet 1996;92:130±134.

40. Swift M, Reitnauer PJ, Morrell D, Chase CL. Breast and othercancers in families with ataxia-telangiectasia. N Engl J Med1987;316:1289±1294.

41. Swift M, Morrell D, Massey RB, Chase CL. Incidence ofcancer in 161 families affected by ataxia-telangiectasia. NEngl J Med 1991;325:1831±1836.

42. Easton DF. Cancer risks in A-T heterozygotes. Int J RadiatBiol 1994;66:S177±S182.

43. Bishop DT, Hopper J. AT-tributable risks? Nat Genet 1997;15:226.

44. FitzGerald M, Bean J, Hegde S, et al. Heterozygous ATMmutations do not contribute to early onset of breast cancer.Nat Genet 1997;15:307±310.

45. Chen J, Birkholtz G, Lindblom P, Rubio C, Lindblom A. Therole of ataxia-telangiectasia heterozygotes in familial breastcancer. Cancer Res 1998;58:1376±1379.

46. Bebb G, Glickman B, Gelmon K, Gatti R. ``AT risk'' for breastcancer. Lancet 1997;349:1784±1785.

47. Werneke U. Ataxia telangiectasia and risk of breast cancer.Lancet 1997;350:739±740.

48. Ramsay J, Birrell G, Lavin M. Testing for mutations of theataxia telangiectasia gene in radiosensitive breast cancerpatients. Radiother Oncol 1998;47:125±128.

49. Larson GP, Ahang G, Ding S, et al. An allelic variant at theATM locus is implicated in breast cancer susceptibility.Genetic Testing 1997/98;1:165±170.

50. Barlow C, Hirotsune S, Paylor R, et al. Atm-de®cient mice: Aparadigm of ataxia telangiectasia. Cell 1996;86:159±171.

51. Westphal C, Rowan S, Schmaltz C, Elson A, Fisher D, LederP. Atm and p53 cooperate in apoptosis and suppression oftumorigenesis, but not in resistance to acute radiationtoxicity. Nat Genet 1997;16:397±401.

52. Herzog K-H, Chong MJ, Kapsetaki M, Morgan JI, McKinnonPJ. Requirement of Atm in ionizing radiation-induced celldeath in the developing central nervous system. Science1998;280:1089±1091.

53. Westphal C, Hoyes KP, Canman CE, et al. Loss of atmradiosensitizes multiple p53 null tissues. Cancer Res 1998;58:5637±5639.

54. Barlow C, Eckhaus MA, Schaffer AA, Wynshaw-Boris A.Atm haploinsuf®ciency results in increased sensitivity tosublethal does of ionizing radiation in mice. Nat Genet1999;21:359±360.

55. Nishisho I, Nakamura Y, Miyoshi Y, et al. Mutations ofchromosome 5q21 genes in FAP and colorectal-cancerpatients. Science 1991;253:665±669.

56. Groden J, Thliveris A, Samowitz W, et al. Identi®cation andcharacterization of the familial adenomatous polyposis-coligene. Cell 1991;66:589±600.

57. Woodage T, King SM, Wacholder S, et al. The APC I1307Kallele and cancer risk in a community-based study ofAshkenazi Jews. Nat Genet 1998;20:62±65.

58. Redston M, Nathanson KL, Yuan ZQ, et al. The APCI1307K allele and breast cancer risk. Nat Genet 1998;20:13±14.

59. Fodde R, Edelmann W, Yang K, et al. A targeted chain-termination mutation in the mouse APC gene results inmultiple intestinal tumors. Proc Natl Acad Sci USA1994;91:8969±8973.

60. Su L-K, Kinzler KW, Vogelstein B, et al. Multiple intestinalneoplasia caused by a mutation in the murine homolog ofthe APC gene. Science 1992;256:668±670.

61. Moser AR, Pitot HC, Dove WF. A dominant mutation thatpredisposes to multiple intestinal neoplasia in the mouse.Science 1990;247:322±324.

62. Moser AR, Mattes EM, Dove WF, Lindstrom MJ, Haag JD,Gould MN. ApcMin, a mutation in the murine Apcgene, predisposes to mammary carcinomas and focalalveolar hyperplasias. Proc Natl Acad Sci USA 1993;90:8977±8981.

63. van der Houven van Oordt CW, Smits R, Williamson SLH, etal. Intestinal and extra-intestinal tumor multiplicities in theApc1638N mouse model after exposure to x-rays. Carcino-genesis 1997;18:2197±2203.

64. Ullrich RL, Jernigan MC, Satter®eld LC, Bowles ND.Radiation carcinogenesis: Time-dose relationships. RadiatRes 1987;111:179±184.

65. Ullrich RL, Bowles ND, Satter®eld LC, Davis CM. Strain-dependent susceptibility to radiation-induced mammarycancer is a result of differences in epithelial cell sensitivity totransformation. Radiat Res 1996;146:353±355.

148 BENNETT

66. DeOme KB, Faulkin LJ Jr, Bern HA, Blair PB. Development ofmammary tumors from hyperplastic alveolar nodulestransplanted into gland-free mammary fat pads of femaleC3H mice. Cancer Res 1959;19:515±520.

67. Ponnaiya B, Cornforth MN, Ullrich RL. Radiation-inducedchromosomal instability in BALB/c and C57BL/6 mice: The

difference is as clear as black and white. Radiat Res1997;147:121±125.

68. Haston CK, Travis EL. Murine susceptibility to radiation-induced pulmonary ®brosis is in¯uenced by a genetic factorimplicated in susceptibility to bleomycin-induced pulmonary®brosis. Cancer Res 1997;57:5286±5291.

BREAST CANCER: GENETICS AND RADIATION 149