Progression from hormone dependence to autonomy in mammary tumors as an in vivo manifestation of sequential clonal selection.

The natural history of breast cancer with respect to its progression from hormone dependence to autonomy was studied by successively transplanting the earliest possible form of a rat mammary adenocarcinoma in syngeneic rats and isolating sublines of this tumor manifesting new endocrinological and other biological characteristics over a period of 15 years. The original, fully mannotropin-dependent tumor MT-W9, whose growth is dependent entirely on pharmacological levels of mannotropin supplied by an extraneous source, gave rise to an estrogen-dependent variant, MT-W9A. This MT-W9A growns only in normal adult female hosts and regresses promptly upon oophorectomy. Subsequently, this tumor produced a subline, the fully autonomous MT-W9B, which grows well in any syngeneic rats regardless of their hormonal status. The third subline derived from the autonomous tumor was designated MT-W9C, the androgen-responsive line, because it growns better in male than in female rats. Having reversed its original female preference, it might also be characterized as reversely responsive. Chromosomal analysis of these 4 tumors disclosed 4 distinct stem cell lines, but each tumor also contained small numbers of cells from other stem lines. The progression from mammotropin dependence to androgen responsiveness in this mammary tumor system seems to have been accomplished by merely shifting from 1 stem line to another in an orderly sequence, and it appears to be an irreversible process. In addition to the hormone dependency, the progression of the tumor is accompanied by a gradual increase of cachexia-producing effects on the host that may be related to the immunogenicity of tumor cells. These 4 distinct hormonal characteristics encompass the entire known spectrum of breast cancer in man and animals with the exception of the metastasizing property. These tumors are being studied by many investigators and are maintained vertically and horizontally in syngeneic rats by us. The hormonal and cytogenetic characteristics of each stem cell line have been stable for over a decade.