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Journal of Mammary Gland Biology and Neoplasia (JMGBN) PP030-290984 January 4, 2001 16:12 Style file version Nov. 07, 2000

Journal of Mammary Gland Biology and Neoplasia, Vol. 5, No. 4, 2000

Introduction: Models of Premalignant Breast Disease

D. Craig Allred1,2 and Daniel Medina1

Most invasive breast cancers (IBC)3 appear toarise over long periods of time from certain pre-existing benign lesions. Of the many types of benignlesion in the human breast, only a few appear to havesignificant premalignant potential. The best character-ized of these include atypical hyperplasias and in situcarcinomas, and both categories are probably wellalong on the evolutionary pathway to IBC. Far lessis known about earlier premalignant alterations.

All types of premalignant breast lesions arerelatively common, but only a small proportionprogress to IBC. Currently, their histological featuresdefine these lesions and their prognosis is impreciselyestimated from indirect epidemiological evidence.Although lesions within specific categories lookalike, they must possess underlying biological dif-ferences causing some to remain stable while othersprogress. Recent studies suggest that they evolve byhighly diverse and complex genetic and epigeneticmechanisms.

Research into these altered pathways is likely tolead to identification of specific defects that can be tar-geted to prevent the development and progression ofpremalignant lesions before they become cancerous.For example, nearly all atypical ductal hyperplasias(ADH) over-express estrogen receptor (ER) in nearlyall cells, suggesting that highly ER-positive lesionsmay be particularly susceptible to hormonal therapy.In the recently completed NSABP P-1 chemopre-vention trial, patients with ADH receiving tamoxifenshowed a dramatic (85%) reduction in breast cancerincidence. The success of this trial in patients withADH is proof-of-principle that targeting biological

1 Breast Center and Department of Pathology and Department ofCell Biology, Baylor College of Medicine, Houston, Texas 77030.

2 To whom correspondence should be addressed: Breast Center,Baylor College of Medicine, One Baylor Plaza, MS600, Houston.Texas 77030. E-mail: dcallred@bcm.tmc.edu

3 Abbreviations: invasive breast cancer (IBC); atypical ductal hy-perplasia (ADH); estrogen receptor (ER).

alterations in premalignant lesions is a rational strat-egy for the chemoprevention of breast cancer.

The National Cancer Institute recently spon-sored a review of their breast cancer portfolio tohelp identify areas of high priority for future direc-tions and funding in breast cancer research. The en-suing report of the Progress Review Group (Chart-ing the Course: Priorities for Breast Cancer Research.August, 1999) identified premalignant breast diseaseas one of a dozen top priorities, and the Instituteresponded by providing significantly increased fund-ing for this area, among others. The report specifi-cally identified the need for more and better in vivomodel systems of premalignant breast disease. Suc-cess in preventing the development and progressionof premalignant lesions has the potential to preventthe majority of breast cancers, a revolutionary ratherthan evolutionary achievement.

Most of our current knowledge about the biolog-ical characteristics of human premalignant breast dis-ease comes from correlative studies of formalin-fixed,paraffin-embedded, clinical samples that are micro-scopic in size and difficult to obtain. Progress at a morefundamental mechanistic level has been hampered inthe past by limited availability of truly representativecell lines and animal models. Fortunately, redirectedemphasis on the early stages of tumor progression inexisting animal models of breast cancer, and the re-cent development of many newer models through ge-netic engineering, have lead to the emergence of toolswhich collectively begin to encompass the biologicaldiversity of human premalignant breast disease andset the stage for a quantum leap in progress in thenot-too-distant future. This Journal issue is devotedto reviews of premalignant breast disease. The articlesemphasize its biological characteristics and, more im-portantly, the models that are now available to sup-port the studies necessary to conquer breast cancerthrough prevention.

The first paper, by Page and colleagues, providesa historical perspective of human premalignant breast

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340 Allred and Medina

disease from the histopathological and epidemiolog-ical viewpoints that originally defined this field of re-search. Allred and Mohsin then review our currentknowledge of the biological characteristics of prema-lignant lesions in the human breast. This knowledge,gained primarily from correlative studies of clinicaltissue samples, provides guidance to basic scientistsdeveloping the models for laboratory studies, ensur-ing that such models reflect alterations important inhuman disease. In turn, discoveries initially made inlaboratory studies of animal models have been laterverified as important in human disease, completinga necessary and important circle of collaboration.The remaining contributions represent in-depth re-views of the general types of cell and animal mod-els available for laboratory-based research into theevolution of premalignant lesions to breast cancer.They include a discussion by Stampfer and Yaswen ofin vitro transformed human mammary epithelial celllines that possess biological alterations that appear tobe important during the early stages of breast can-cer development. Miller provides an excellent reviewof xenograft models of premalignant breast disease,with particular emphasis on the MCF10AT model,which has unique stem cell properties and the abil-ity to histologically mimic early premalignant lesionssuch as usual hyperplasias and ADH. Articles byMedina and by Thompson and Singh review viral-induced and carcinogen-induced mouse and rat mod-els of premalignancy in the breast. These models werethe first to provide substantial insight into the biolog-ical causes of early breast cancer evolution. Cardiffand colleagues give an outstanding overview of ge-netically engineered mouse models of mammary in-traepithelial neoplasia; these models that have enor-

mous potential to mimic human premalignant breastlesions both morphologically and biologically.

In the near future, with these models in hand,there are several important goals to achieve. It is crit-ical, for example, to obtain detailed genetic charac-terizations of all these models to determine how wellthey represent the human condition. Having said this,our knowledge of the genetic and biological char-acteristics of human premalignant breast disease issketchy at best. Microarray analysis and other novelhigh throughput technologies have the potential togenerate a highly detailed genetic description of pre-malignant breast disease from human tissue samples.These highly efficient technologies can also be appliedto the models themselves to help elucidate all of thesteps in the pathways from normal cells, to prema-lignant cells, to fully developed breast cancer—stepswhich can then be validated as playing a role in hu-man disease. Again this cycle emphasizes the need forclose collaboration between basic and clinical scien-tists if progress is to be made. Special attention mustbe paid to the earliest biological alterations in mod-els of premalignancy because, if they are shown to beimportant in human disease, they are likely to be theeasiest to control or prevent. In addition to identifyingcritical defects, animal models also provide a mediumfor the safe and efficient testing of various drugs andother strategies to prevent the development and pro-gression of premalignant lesions to breast cancer. Suc-cess in the laboratory will eventually be translated toclinical studies. If we are to eliminate breast cancer,it is more rational to think about preventing it fromdeveloping than to think it can be cured once it has de-veloped. The tools are becoming available to achievethis goal.