estrogens regulate this pathway or act differently than endogenous estrogens? Are local growth factors and the newly detected extracellular matrix proteins, such as tenascin, important in the etiology of breast cancer? If not, can they serve at least as markers of the stage or etiology of the disease? Are oncogenes always involved ultimately in breast cancer (regardless of the initial insult)? Will the different oncogenes that are possibly involved act through the same final common pathway to cause transformation? Questions such as these, and many others, need to be vigorously pursued in a multidisciplinary setting to expand our understanding of breast biology in a way that will be relevant to the etiology of breast cancer.

A number of different genetic aberrations have been seen in breast cancers, but in each instance, the lesions are found only in a proportion of all such cancers. Preliminary observations suggest that some lesions may be coordinately expressed; thus, it may be possible to define subsets of breast cancer by their constellations of molecular aberrations. Breast cancers are unusual in that tumors of similar histology and staging may have widely varying clinical courses. This variability and the existence of molecular subsets suggest that breast cancer may be more than one disease, each with differing etiologies. If so, insights into putative etiologic agents—for example, oral contraceptives —may be acquired by determining whether their use is correlated with specific molecular breast cancer subsets.

With respect to oral contraceptive formulations (see Appendix C), four questions emerge as immediate research priorities: Do individual variations in blood levels in ethinyl estradiol and the progestin component of oral contraceptives affect the risk of breast cancer? What are the effects of the progestin component of oral contraceptives in modulating estrogen action? Do the inherent androgenic or antiestrogenic properties of different oral contraceptive formulations affect normal breast tissue response? How will the overall estrogen dominance of the new oral contraceptives affect breast tissue response?

Cancerous breast tissue has been well studied. For the 1990s, intense focus on normal rather than neoplastic epithelium is warranted. Because the significant issue concerning oral contraceptives is their effect on normal breast epithelium, the committee emphasizes the importance of concentrating on the largest gap in present knowledge: the transformation of benign to malignant epithelium.



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