Orthotopic Tissue Interactions

Most of what is known about the role of mammary tissue interactions in progression is based on studies with preneoplastic mouse mammary tissues. These lesions require normal mammary stroma for growth and progression to carcinoma but are inhibited by normal mammary epithelium (DeOme et al., 1959,1978; Faulkin and DeOme, 1960; Daniel et al., 1968; Medina, 1975, 1976, 1996). Mouse mammary tumor cells still respond to stroma but are no longer stroma-dependent and are stimulated, rather than inhibited, by normal mammary epithelium (Miller et al., 1981; Miller and Mclnerney, 1988). Furthermore, mammary tumors metastasize more readily from mammary gland than from other sites (Miller, 1981; Unemori et al., 1984; Vaage, 1988). The growth and metastasis of xenografted human breast cancer cells are also enhanced by implantation into mammary fatpads in nude mice (Price, 1990; Price et al., 1990).

These observations suggest that the cleared, that is, epithelium-free, mammary fatpads of immune-deficient mice might be ideal sites for xenograft transplants of normal and preneoplastic human breast epithelium. An early study reported successful transplantation of pieces of breast fibrocystic disease into cleared fatpads (Outzen and Custer, 1975). Three cases were described and serial transplantation through four transplant generations of a lesion, described as cystic hyperplasia with ductal proliferation, indicated that 16 volume doublings were obtained. Another study found that normal-appearing lobules persisted nearly as well at subcutaneous sites (54 of 78 implanted lesions; 69%) as in mammary fatpads (51/64; 80%) of nude mice (Jensen and Wellings, 1976).

None of the explants increased in size, but intraductal proliferation occurred more readily in fatpads (25/51; 49%) than at subcutaneous sites (4/54; 7%). Histologically normal lobules from cancer patients were no more likely to proliferate than lobules from noncancerous patients when age was taken into consideration (nearly all noncancerous patients were under 50).

However, lobules from cancer patients over age 50 were significantly more likely to proliferate than lobules from cancer patients under age 50 (15/28 vs. 5/33; 54% vs. 15%).

Another point of interest is that 20/22 (91%) cancer-associated lobules that proliferated were vascularized as compared with only 19/48(40%) of lobules that failed to do so. For lobules from noncancerous breasts, vascularization was observed in 3/7 (43%)prolifcrating lobules and in 9/28 (32%) lobules that did not proliferate. Thus, angiogenic activity may be indicative of precursor proliferative breast lesions.

Fred Raymond Miller
Advances in Oncobiology

References