Mills Ch3 Breast

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CHAPTER 3:  Breast

breast epithelium may show HER2 protein overexpression, p53 protein accumulation, or p53 mutations. Of note p53 alterations have been identified more frequently in normal epithelium adjacent to breast carcinomas that are ER, PR and HER2 negative (“triple negative”), and/or in BRCA1 mutation carriers raising the possibility that this “p53 sig- nature” may confer a predisposition to p53-associated— high-grade carcinomas (76,77). The antiapoptotic protein bcl-2 is consistently expressed by normal breast epithelial cells (78). S-100 pro- tein is strongly expressed by normal myoepithelial cells and variably expressed by mammary epithelial cells (79). Epi- thelial cells also show variable expression for casein (80), α -lactalbumin (81), gross cystic disease fluid protein-15 (82), mammaglobin (83), GATA-3 and c-Kit (CD117) (84), among other proteins. As noted earlier, cytokeratins 7, 8, 18, and 19 (20–24) are typically expressed by epithelial cells, whereas myoepithelial cells express cytokeratins 5/6, 14, and 17 (20–24,31). Molecular Markers The ability to evaluate DNA, RNA, and protein using the modern tools of molecular biology, particularly when guided by such techniques as laser capture microdissection (85), are enhancing our understanding of breast tumorigenesis and may even serve to redefine what constitutes “normal.” For example, a number of studies have shown that histo- logically normal TDLUs can exhibit an abnormal geno- type, characterized by loss of heterozygosity (86,87), allelic imbalance (88,89) at various chromosomal loci, or altered gene expression profiles (90). At this time, however, the sig- nificance of these genetic and molecular alterations in his- tologically normal breast tissue remains to be determined. Studies of normal breast tissue using these techniques will also help to further define the presence and nature of pro- genitor cells or stem cells and their role in breast develop- ment and carcinogenesis (23,91–93), as well as patterns of gene and protein expressions that distinguish normal from abnormal breast tissue and cells (94–97). CONCLUSION The histologic features of the normal breast are dynamic and vary with age and hormonal milieu, among other fac- tors. An understanding of normal breast histology is essen- tial to permit the reliable distinction between physiologic changes and pathologic alterations.

FIGURE 3.19  Immunostain for estrogen receptor- α (ER α ) in a normal lobule. A minority of epithelial cells show nuclear staining.

patches of ER α -positive cells also increases with age and with involutional changes (69). In addition, the proportion of ER α -positive proliferating cells increases with age (69). In premenopausal women, ER α expression varies with the phase of the menstrual cycle, being higher in the follicular than in the luteal phase (70). Myoepithelial cells do not show ER α immunoreactivity (33). A second form of ER, ER β , is also expressed in nor- mal breast tissue. Expression of ER β has been observed not only in epithelial cells of ducts and lobules, but also in myoepithelial cells, endothelial cells, and stromal cells (70–73). The expression of this form of ER does not seem to vary with the phase of the menstrual cycle. It has been speculated that the relative levels of ER β and ER α may be important in determining the risk of breast cancer devel- opment, and that higher levels of ER β relative to ER α are protective against neoplastic progression in the breast (71). However, additional studies are needed to more clearly elucidate the role of ER β in normal breast physiol- ogy and in breast cancer pathogenesis and to determine which ER β isoform provides the greatest specificity in this regard (74). Expression of PR has not been as extensively studied in normal breast tissue as has ER. Like ER α , PR is expressed in the nuclei of ductal and lobular epithelium. However, in contrast to ER α expression, PR expression does not seem to vary with the menstrual cycle phase (70).

Other Biomarkers and Immunophenotypic Features

Expression of a wide variety of biomarkers has been studied in benign breast tissue (75) and a comprehensive review of these is beyond the scope of this chapter. However, a cou- ple of these merits brief mention, though the clinical sig- nificance of the findings is as yet uncertain. Rarely, normal

REFERENCES

1. Jochelson M. Breast cancer imaging: the future. Semin Oncol 2001;28(3):221–228.