Biological Features of Premalignant Disease in the Human Breast

Most human invasive breast cancers (IBCs)4 arise from preexisting benign lesions. There are many types of benign lesions in the human breast and only a few appear to have significant premalignant potential (atypical hyperplasias and in situ carcinomas). These lesions are relatively common and only a small proportion progress to IBC. They are currently defined by their histological features and their prognosis is imprecisely estimated from indirect evidence based on epidemiological studies. Although lesions within specific categories look alike, they must possess morphologically silent biological differences motivating some to remain stable and others to progress. Understanding the biological changes responsible for the development and progression of premalignant disease is a very active area of medical research. Progress in this area may provide new opportunities for breast cancer prevention by providing strategies to treat premalignant lesions before they develop or become cancerous. A large number of biological features have been evaluated in this setting during the past decade. This review discusses a few features that appear to be particularly important and have been studied in a relatively comprehensive manner.

[1]  F. W. Foote,et al.  Comparative Studies of Cancerous Versus Noncancerous Breasts. , 1945, Annals of surgery.

[2]  L. Brinton,et al.  Breast cancer risk associated with proliferative breast disease and atypical hyperplasia , 1993, Cancer.

[3]  D M Barnes,et al.  Overexpression of the c-erbB-2 oncoprotein: why does this occur more frequently in ductal carcinoma in situ than in invasive mammary carcinoma and is this of prognostic significance? , 1992, European journal of cancer.

[4]  S. Hilsenbeck,et al.  A hypersensitive estrogen receptor-alpha mutation in premalignant breast lesions. , 2000, Cancer research.

[5]  C. Potter,et al.  The neu-protein and breast cancer , 2004, Virchows Archiv.

[6]  N. Phillips,et al.  Allelotyping of ductal carcinoma in situ of the breast: deletion of loci on 8p, 13q, 16q, 17p and 17q. , 1995, Cancer research.

[7]  W. Dupont,et al.  Transforming Growth Factor-β and Breast Cancer Risk in Women With Mammary Epithelial Hyperplasia. , 1999, Journal of the National Cancer Institute.

[8]  J. Sloane,et al.  neu overexpression correlates with extent of disease in large cell ductal carcinoma in situ of the breast. , 1995, Human pathology.

[9]  W. Lee,et al.  Apoptosis occurs more frequently in intraductal carcinoma than in infiltrating duct carcinoma of human breast cancer and correlates with altered p53 expression: detected by terminal‐deoxynucleotidyl‐transferase‐mediated dUTP‐FITC nick end labelling (TUNEL) , 1997, Histopathology.

[10]  P. Validire,et al.  Mammographically-detected ductal in situ carcinoma of the breast analyzed with a new classification. A study of 127 cases: correlation with estrogen and progesterone receptors, p53 and c-erbB-2 proteins, and proliferative activity. , 1994, Seminars in diagnostic pathology.

[11]  C. Potter.  The neu-oncogene: More than a prognostic indicator? , 1994 .

[12]  A. Sahin,et al.  Comparative allelotype of in situ and invasive human breast cancer: high frequency of microsatellite instability in lobular breast carcinomas. , 1995, Cancer research.

[13]  O. Kallioniemi,et al.  Immunohistochemical determination of estrogen and progesterone receptors in human breast carcinoma. Correlation with histopathology and dna flow cytometry , 1990, Cancer.

[14]  L. Cupples,et al.  Detection of monoclonal microsatellite alterations in atypical breast hyperplasia. , 1996, The Journal of clinical investigation.

[15]  L. Liotta,et al.  Identical allelic loss on chromosome 11q13 in microdissected in situ and invasive human breast cancer. , 1995, Cancer research.

[16]  M. Vijver,et al.  The expression of the neu oncogene product in breast lesions and in normal fetal and adult human tissues , 1989, Histopathology.

[17]  M. Merino,et al.  Loss of heterozygosity on chromosome 11 q 13 in lobular lesions of the breast using tissue microdissection and polymerase chain reaction , 1997 .

[18]  D. Craig Allred,et al.  Molecular genetic studies of early breast cancer evolution , 2004, Breast Cancer Research and Treatment.

[19]  N. Katagata,et al.  [Pathological characterization of atypical ductal hyperplasia of the breast]. , 1995, Gan to kagaku ryoho. Cancer & chemotherapy.

[20]  N. Phillips,et al.  Allelic loss and the progression of breast cancer. , 1995, Cancer research.

[21]  J. Nesland,et al.  TP53 alterations in atypical ductal hyperplasia and ductal carcinomain situ of the breast , 2005, Breast Cancer Research and Treatment.

[22]  W. Dupont,et al.  p53 mutations are confined to the comedo type ductal carcinoma in situ of the breast. Immunohistochemical and sequencing data. , 1994, Laboratory investigation; a journal of technical methods and pathology.

[23]  W. Dupont,et al.  Breast cancer risk of lobular-based hyperplasia after biopsy: "ductal" pattern lesions. , 1986, Cancer detection and prevention.

[24]  J. Meyer,et al.  Thymidine labeling index and Ki-67 growth fraction in lesions of the breast. , 1989, The American journal of pathology.

[25]  S. Masood,et al.  Potential value of hormone receptor assay in carcinoma in situ of breast. , 1990, American journal of clinical pathology.

[26]  S. Hirohashi,et al.  p53 Mutations and c‐erbB‐2 Amplification in Intraductal and Invasive Breast Carcinomas of High Histologic Grade , 1993, Japanese journal of cancer research : Gann.

[27]  A. Thompson,et al.  Allelic loss on a chromosome 17 in ductal carcinoma in situ of the breast. , 1993, Cancer research.

[28]  W. Dupont,et al.  Intraductal carcinoma of the breast: Follow‐up after biopsy only , 1982, Cancer.

[29]  A. Vecchione,et al.  Correlation between ploidy status, Erb-B2 and p53 immunohistochemical expression in primary breast carcinoma. , 1995, Analytical and quantitative cytology and histology.

[30]  L. Liotta,et al.  Analysis of loss of heterozygosity on chromosome 11q13 in atypical ductal hyperplasia and in situ carcinoma of the breast. , 1997, The American journal of pathology.

[31]  M. Gnant,et al.  p53 protein expression, cell proliferation and steroid hormone receptors in ductal and lobular in situ carcinomas of the breast. , 1997, European journal of cancer.

[32]  J. Meyer.  Cell kinetics of histologic variants ofin situ breast carcinoma , 2005, Breast Cancer Research and Treatment.

[33]  F. Schmitt,et al.  Multistep progression from an oestrogen-dependent growth towards an autonomous growth in breast carcinogenesis. , 1995, European journal of cancer.

[34]  L. Melton,et al.  HER-2/neu amplification in benign breast disease and the risk of subsequent breast cancer. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  E. Magri,et al.  Biophenotypes of breast carcinoma in situ defined by image analysis of biological parameters. , 1996, Pathology, research and practice.

[36]  D. Weiner,et al.  Immunohistochemical evaluation of c-erbB-2 oncogene expression in ductal carcinoma in situ and atypical ductal hyperplasia of the breast. , 1990, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[37]  S. Schnitt,et al.  bcl‐2 expression in the spectrum of preinvasive breast lesions , 1996 .

[38]  S. Schnitt,et al.  Extensive apoptosis in ductal carcinoma in situ of the breast , 1996, Cancer.

[39]  P. Rudland.  Epithelial stem cells and their possible role in the development of the normal and diseased human breast. , 1993, Histology and histopathology.

[40]  R. Perry,et al.  p53 protein expression in ductal carcinoma in situ (DCIS) of the breast , 1997, Breast Cancer Research and Treatment.

[41]  J. Costantino,et al.  Pathologic findings from the national surgical adjuvant breast project (NSABP) protocol B‐17: Intraductal carcinoma (ductal carcinoma in situ) , 2006 .

[42]  D. Barnes,et al.  Relationship between c-erbB-2 immunoreactivity and thymidine labelling index in breast carcinomain situ , 1991, Breast Cancer Research and Treatment.

[43]  J. Papadimitriou,et al.  Microsatellite instability and loss of heterozygosity in mammary carcinoma and its probable precursors. , 1997, British Journal of Cancer.

[44]  D. Faller,et al.  Microsatellite alterations indicating monoclonality in atypical hyperplasias associated with breast cancer. , 1997, Human pathology.

[45]  A. Thor,et al.  Loss of Heterozygosity in Normal Tissue Adjacent to Breast Carcinomas , 1996, Science.

[46]  H. Roels,et al.  Feulgen DNA content and mitotic activity in proliferative breast disease. A comparison with ductal carcinoma in situ , 1987, Histopathology.

[47]  M. J. van de Vijver,et al.  Neu-protein overexpression in breast cancer. Association with comedo-type ductal carcinoma in situ and limited prognostic value in stage II breast cancer. , 1988, The New England journal of medicine.

[48]  M. Stratton,et al.  Atypical ductal hyperplasia of the breast: clonal proliferation with loss of heterozygosity on chromosomes 16q and 17p. , 1995, Journal of clinical pathology.

[49]  J. Minna,et al.  Analysis of the FHIT gene and FRA3B region in sporadic breast cancer, preneoplastic lesions, and familial breast cancer probands. , 1997, Cancer research.

[50]  H. Yoshida,et al.  Expression of p53 protein in benign epithelial hyperplasia, atypical ductal hyperplasia, non-invasive and invasive mammary carcinoma: an immunohistochemical study , 2004, Virchows Archiv.

[51]  W. McGuire,et al.  Overexpression of HER-2/neu and its relationship with other prognostic factors change during the progression of in situ to invasive breast cancer. , 1992, Human pathology.

[52]  B. Henderson,et al.  Estrogens as a cause of human cancer: the Richard and Hinda Rosenthal Foundation award lecture. , 1988, Cancer research.

[53]  T. Anderson,et al.  Proliferative and secretory activity in human breast during natural and artificial menstrual cycles. , 1988, The American journal of pathology.

[54]  M. Pike,et al.  Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk. , 1993, Epidemiologic reviews.

[55]  A. Levine.  p53, the Cellular Gatekeeper for Growth and Division , 1997, Cell.

[56]  M. Indelli,et al.  Modulation of biomarkers in minimal breast carcinoma , 1998, Cancer.

[57]  R. Laucirica,et al.  p53 accumulation in benign breast biopsy specimens. , 1995, Human pathology.

[58]  B. Gusterson,et al.  c-erbB-2 expression in benign and malignant breast disease. , 1988, British Journal of Cancer.

[59]  R. Coombes,et al.  Breast Estrogen and Progesterone Receptors in the Normal Female Updated Version , 2006 .

[60]  J. A. Andersen,et al.  Breast cancer and atypia among young and middle-aged women: a study of 110 medicolegal autopsies. , 1987, British Journal of Cancer.

[61]  A. Kreutner,et al.  Lobular carcinoma in situ , 1980, Journal of surgical oncology.

[62]  T. Longacre,et al.  A Correlative Morphologic Study of Human Breast and Endometrium in the Menstrual Cycle , 1986, The American journal of surgical pathology.

[63]  T. Walsh,et al.  Loss of heterozygosity at chromosome 6q in preinvasive and early invasive breast carcinomas. , 1997, British Journal of Cancer.

[64]  I. Ellis,et al.  Ductal Carcinoma In-Situ Of The Breast: A new simplified histological classification. Association between cellular proliferation and c-erbB-2 protein expression , 1992 .

[65]  F. Schmitt,et al.  Ductal carcinoma in situ of the breast. Histologic categorization and its relationship to ploidy and immunohistochemical expression of hormone receptors, p53, and c‐erbB‐2 protein , 1995, Cancer.

[66]  D. Lane,et al.  Abnormal expression of wild type p53 protein in normal cells of a cancer family patient , 1992, The Lancet.

[67]  J. Varley,et al.  Frequent alterations of chromosome 1 in ductal carcinoma in situ of the breast. , 1995, Oncogene.

[68]  S. Syrjänen,et al.  Implications of the p53 tumor-suppressor gene in clinical oncology. , 1995, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[69]  G. Greene,et al.  Immunocytochemical estrogen and progestin receptor assays in breast cancer with monoclonal antibodies. Histopathologic, demographic, and biochemical correlations and relationship to endocrine response and survival , 1990, Cancer.

[70]  K. Horwitz,et al.  Nuclear receptor coactivators and corepressors. , 1996, Molecular endocrinology.

[71]  C K Redmond,et al.  Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. , 1999, Journal of the National Cancer Institute.

[72]  C. Alpers,et al.  The prevalence of carcinoma in situ in normal and cancer-associated breasts. , 1985, Human pathology.

[73]  C. Potter,et al.  The p185erbB2 protein is localized on cell organelles involved in cell motility , 1993, Clinical & Experimental Metastasis.

[74]  J. Marks,et al.  Genetic basis for p53 overexpression in human breast cancer. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[75]  I. Ellis,et al.  Oestrogen receptor expression in ductal carcinoma in situ of the breast: relationship to flow cytometric analysis of DNA and expression of the c-erbB-2 oncoprotein. , 1993, British Journal of Cancer.

[76]  J. Bártková,et al.  Immunohistochemical demonstration of c-erbB-2 protein in mammary ductal carcinoma in situ. , 1990, Human pathology.

[77]  H M Jensen,et al.  An atlas of subgross pathology of the human breast with special reference to possible precancerous lesions. , 1975, Journal of the National Cancer Institute.

[78]  I. Ellis,et al.  Flow cytometric and histological analysis of ductal carcinoma in situ of the breast , 1990, The British journal of surgery.

[79]  W. Gullick,et al.  OVEREXPRESSION OF THE c-erbB-2 ONCOPROTEIN IN HUMAN BREAST CARCINOMAS: IMMUNOHISTOLOGICAL ASSESSMENT CORRELATES WITH GENE AMPLIFICATION , 1987, The Lancet.

[80]  Rochelle L. Garcia,et al.  C‐ERBB‐2 oncogens protein in In situ and invasive lobular breast neoplasia , 1991 .

[81]  A. Miller,et al.  Immunohistochemical detection of c-erbB-2 and p53 in benign breast disease and breast cancer risk. , 1998, Journal of the National Cancer Institute.

[82]  R. Kurman,et al.  Clinical significance of Her-2/neu overexpression in uterine serous carcinoma. , 2006, Gynecologic oncology.

[83]  J. Meyer,et al.  Cell proliferation in fibrocystic disease and postmenopausal breast ducts measured by thymidine labeling , 1982, Cancer.

[84]  J. Russo,et al.  Influence of age and gland topography on cell kinetics of normal human breast tissue. , 1987, Journal of the National Cancer Institute.

[85]  L. Skoog,et al.  Immunohistochemical c-erbB-2 protooncogene expression and nuclear DNA content in human mammary carcinoma in situ. , 1992, American journal of clinical pathology.

[86]  E. Bastounis,et al.  Immunohistochemical detection of oestrogen receptors in ductal carcinoma in situ of the breast. , 1996, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[87]  D. Giri,et al.  Oestrogen receptors in benign epithelial lesions and intraduct carcinomas of the breast: an immunohistological study , 1989, Histopathology.

[88]  I. Ellis,et al.  High levels of allele loss at the FHIT and ATM genes in non-comedo ductal carcinoma in situ and grade I tubular invasive breast cancers. , 1996, Cancer research.

[89]  R. Elledge,et al.  The p53 tumor suppressor gene in breast cancer , 2004, Breast Cancer Research and Treatment.

[90]  S J London,et al.  A prospective study of benign breast disease and the risk of breast cancer. , 1992, JAMA.

[91]  R. Simon,et al.  Estrogen receptor values in patients with benign breast disease , 1979, Cancer.

[92]  V. Eusebi,et al.  Immunohistochemical study ofneu protein overexpression in clinging in situ duct carcinoma of the breast , 2005, Virchows Archiv A.

[93]  J. Biggart,et al.  c-erbB-2 overexpression and histological type of in situ and invasive breast carcinoma. , 1992, Journal of clinical pathology.

[94]  H M Jensen,et al.  On the origin and progression of ductal carcinoma in the human breast. , 1973, Journal of the National Cancer Institute.

[95]  S. Ashley,et al.  Immunohistochemical distribution of c‐erbB‐2 in in situ breast carcinoma—a detailed morphological analysis , 1990, The Journal of pathology.

[96]  D. Lane,et al.  Expression of p53 protein in infiltrating and in‐situ breast carcinomas , 1991, The Journal of pathology.

[97]  M. Stratton,et al.  Loss of heterozygosity in lobular carcinoma in situ of the breast , 1995, Clinical molecular pathology.

[98]  E Gabrielson,et al.  Genetic divergence in the clonal evolution of breast cancer. , 1996, Cancer research.

[99]  J. Meyer.  Cell proliferation in normal human breast ducts, fibroadenomas, and other ductal hyperplasias measured by nuclear labeling with tritiated thymidine. Effects of menstrual phase, age, and oral contraceptive hormones. , 1977, Human pathology.

[100]  E. Gabrielson,et al.  Genetic progression, histological grade, and allelic loss in ductal carcinoma in situ of the breast. , 1996, Cancer research.

[101]  W D Dupont,et al.  Risk factors for breast cancer in women with proliferative breast disease. , 1985, The New England journal of medicine.

[102]  A. Zetterberg,et al.  Immunohistochemical expression of the mutant p53 protein and nuclear DNA content during the transition from benign to malignant breast disease. , 1994, Human pathology.

[103]  S. Mucci,et al.  Distribution of estrogen receptor in ductal carcinoma in situ of the breast. , 1993, Surgery.

[104]  David L. Page,et al.  Anatomic indicators (histologic and cytologic) of increased breast cancer risk , 1993, Breast Cancer Research and Treatment.

[105]  K. Nakagawa,et al.  The temporal and spatial vascular endothelial growth factor expression in retinal vasculogenesis of rat neonates. , 1996, Laboratory investigation; a journal of technical methods and pathology.

[106]  L. Norton,et al.  Immunophenotype of intraductal carcinoma. , 1996, Archives of pathology & laboratory medicine.

[107]  Yong-jie Lu,et al.  Comparative genomic hybridization analysis of lobular carcinoma in situ and atypical lobular hyperplasia and potential roles for gains and losses of genetic material in breast neoplasia. , 1998, Cancer research.

[108]  T. Anderson,et al.  Morphological evaluation of cell turnover in relation to the menstrual cycle in the "resting" human breast. , 1981, British Journal of Cancer.

[109]  M. Stratton,et al.  Loss of heterozygosity in ductal carcinoma in situ of the breast , 1995, The Journal of pathology.

[110]  L. Humphrey,et al.  Relationship to benign breast disease to carcinoma of the breast. , 1962, Surgery.

[111]  W. Gregory,et al.  The classification of ductal carcinoma in situ and its association with biological markers. , 1994, Seminars in diagnostic pathology.

[112]  J. Bartek,et al.  Patterns of expression of the p53 tumour suppressor in human breast tissues and tumours in situ and in vitro , 1990, International journal of cancer.

[113]  I. Ellis,et al.  p53 protein expression in mammary ductal carcinoma in situ: relationship to immunohistochemical expression of estrogen receptor and c-erbB-2 protein. , 1993, Human pathology.

[114]  O. Petersen,et al.  Frequency and distribution of estrogen receptor-positive cells in normal, nonlactating human breast tissue. , 1987, Cancer research.

[115]  M. Merino,et al.  Loss of heterozygosity on chromosome 11q13 in lobular lesions of the breast using tissue microdissection and polymerase chain reaction. , 1997, Human pathology.

[116]  L. Skoog,et al.  Receptors for estrogen and progesterone in breast carcinoma in situ. , 1992, Anticancer research.

[117]  J. Smith,et al.  Cell proliferation in the human mammary epithelium. Differential contribution by epithelial and myoepithelial cells. , 1986, The American journal of pathology.

[118]  S. Devries,et al.  Chromosomal alterations in ductal carcinomas in situ and their in situ recurrences. , 2000, Journal of the National Cancer Institute.

[119]  S. Bianchi,et al.  Benign breast disease and breast cancer: A case‐control study in a cohort in italy , 1991, International journal of cancer.

[120]  M. Osborn,et al.  Immunohistochemical profile of invasive lobular carcinoma of the breast: Predominantly vimentin and p53 protein negative, cathepsin D and oestrogen receptor positive , 2005, Virchows Archiv A.

[121]  B. Gusterson,et al.  Identification of myoepithelial cells in human and rat breasts by anti-common acute lymphoblastic leukemia antigen antibody A12. , 1986, Journal of the National Cancer Institute.

[122]  S. Paik,et al.  Pathologic findings from the national surgical adjuvant breast project (protocol 6) I. Intraductal carcinoma (DCIS) , 1986, Cancer.

[123]  A. Howell,et al.  The effect of age and menstrual cycle upon proliferative activity of the normal human breast. , 1988, British Journal of Cancer.

[124]  M. Meguid,et al.  Estrogen receptor expression in benign breast epithelium and breast cancer risk. , 1998, Journal of the National Cancer Institute.

[125]  J. Andersen,et al.  Lobular carcinoma in situ. A long-term follow-up in 52 cases. , 2009 .

[126]  P. O’Connell,et al.  Analysis of loss of heterozygosity in 399 premalignant breast lesions at 15 genetic loci. , 1998, Journal of the National Cancer Institute.

[127]  David L. Page,et al.  Atypical hyperplastic lesions of the female breast. A long‐term follow‐up study , 1985, Cancer.