Kinetic and morphometric responses of heterogeneous populations of experimental breast cancer cells in vivo.

Although the hormone responsiveness of some breast cancers is well known, the differential sensitivity of tumor cell subpopulations to hormonal effects is not well established. These experiments were designed to address this issue using the hormone-responsive N-nitrosomethylurea-induced rat mammary tumor. Rats bearing these tumors were randomly assigned to no treatment, 7-day castration, and 7-day castration followed by 1-, 3-, 7-, and 10-day treatment with estradiol benzoate (5 micrograms) and perphenazine (1 mg) to stimulate prolactin release. Under these conditions, the proportion of different cell populations was estimated with morphometric analysis, while their replicative activity was assessed using [3H]thymidine autoradiography. In tumors of intact rats the fractions of glandular epithelial, myoepithelial, and nonepithelial cells were 88.2%, 3.8%, and 8.0%, respectively. All cell types manifested a similar kinetic response to our hormonal treatments characterized by a drastic decline in the labeling index after castration followed by a progressive increase with hormone repletion which peaked on Day 7 of treatment. The magnitude of the response was, however, greater in the epithelial components of the tumor (glandular and myoepithelial cells), where the peak labeling indices significantly exceeded those observed in the tumors of control intact rats. Castration reduced the proportion of glandular cells while increasing the fractions of myoepithelial and nonepithelial cells. Furthermore, castration reduced the volume of the glandular-epithelial cells by 35%, which accounted for approximately half of the overall tumor volume reduction induced by ovariectomy. These alterations in tumor morphology were partially reversed by hormone repletion. These results underscore the exquisite hormonal sensitivity of different cellular counterparts of this experimental breast cancer with regard to both kinetic and morphological characteristics. They also provide support for stromal-epithelial interaction in the hormonal modulation of breast cancer growth.