However, an argument was made earlier in this review that erbB-2-nQg2iiivQ cribriforming DCIS are more likely to progress to invasive cancer than are erbB-2-posiiivQ cribriform DCIS, whereas erbB-2-positive comedo DCIS are more likely to progress than erbB-2-negative comedo DCIS. If comedo and cribriforming DCIS result from two different complementation groups and DCIS that overexpress erbB-2 are a different group than DCIS that do not, at least four different complementation groups are implicated. It is also interesting that erbB-2 and c-myc are rarely overexpressed simultaneously, a fact that suggests separate complementation groups. Perhaps c-mjc-positive DCIS progression to invasive cancer explains the higher likelihood of erbB-2-ncgaii\Q cribriform DCIS than of erbB-2-posiiivt DCIS to progress to invasive cancer.
A third pattern of genetic alteration with sequential stages of progression is exhibited by ras. Overexpression of ras increases with each successive stage. One possible interpretation is that ras overexpression is an essential element of many complementation groups. An alternative possibility is that ras overexpression is a consequence of several other genetic changes and that many complementation groups include an event that acts through the ras signal transduction pathway.
Finally, a gene may seemingly increase and then decrease at subsequent stages of progression. This appears to be true for ER expression. As suggested for the ras gene, this probably indicates that gene expression is an indicator of other genetic alterations rather than a true member of a complementation group that, in concert, produces invasive breast cancer.
Another level of complexity may involve the differentiation state of the normal breast epithelial cell in which the initial genetic event in a complementation group occurs. It has been suggested that ductules, type 1 lobules, type 2 lobules, type 3 lobules, and type 4 lobules represent successive stages of differentiation with loss of stem cells (Russo and Russo, 1996). The Russos suggest that only type 1 lobules give rise to atypical ductular hyperplasia, DCIS, and invasive ductular carcinoma, that type 2 lobules give rise to atypical lobular hyperplasia and lobular carcinomas, and that type 3 lobules give rise to fibroadenomas, sclerosing adenoses, and apocrine cysts (Russo and Russo, 1996).
Although the task to unravel the complexity of breast cancer genetics is a formidable one, the availability of the MCFIOAT preneoplastic human breast stem cells may provide the tool necessary to test suspected complementation groups directly.
Although technically difficult, it may now be possible not only to overexpress genes following transfection/transduction with appropriate constructs, but also to induce point mutations in endogenous genes via homologous recombination using chimeric nucleotides (Kotani and Kmiec, 1994; Kmiec, 1995; Cole-Strauss et al., 1996; Yoon et al., 1996). It would be foolish to presume that the MCFIOAT will allow detection of all complementation groups. MCFIOAT is already a preneoplastic precursor and may be restricted in the number of routes it can follow. However, identification and verification of even a few such complementation groups would be a significant achievement.
The author gratefully acknowledges the advice and suggestions of Dr. Gloria Heppner. The authors studies have been supported by USPHS grant CA28366 from the National Cancer Institute.
Fred Raymond Miller
Advances in Oncobiology
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