SECRETED GROWTH-FACTORS FROM ESTROGEN RECEPTOR-NEGATIVE HUMAN-BREAST CANCER DO NOT SUPPORT GROWTH OF ESTROGEN RECEPTOR-POSITIVE BREAST-CANCER IN THE NUDE-MOUSE MODEL

Estrogen receptor (ER)-negative MDA-231 human breast cancer cells have been shown to secrete high concentrations of several growth factors including transforming growth factor-alpha and insulin-like growth factor I, which could have important autocrine or paracrine growth regulatory functions and, additionally, could explain the rapid autonomous growth of these cells. In contrast, the hormone-responsive, ER-positive MCF-7 cells secrete levels of these factors constitutively. Since estrogen treatment increases secretion of these growth factors in MCF-7 cells, it has been postulated that these growth factors mediate estrogen''s growth effects through an autocrine mechanism. To test this hypothesis we reasoned that growth factors supplied by MDA-231 cells should support growth of MCF-7 cells in an estrogen-depleted environment. Inoculation of castrated female athymic nude mice with MDA-231 cells resulted in rapid tumor growth. However, MDA-231 tumors did not support growth of MCF-7 cells inoculated on the opposite flank by an endocrine mechanism; MCF-7 tumors required estrogen supplementation for growth. To determine if MDA-231 cells could support MCF-7 growth by a paracrine mechanism, various mixtures of the two cell lines were coinoculated at the same site in castrated or in estrogen-supplemented mice. ER was not detectable in tumors derived from a mixed inoculum, indicating the absence of MCF-7 cell growth. Furthermore, DNA flow cytometry of these tumors revealed only a single G1 peak representative of MDA-231 cells in estrogen-deprived mice. On the other hand, two distinct G1 peaks representing both MDA-231 and MCF-7 cells were detected in tumors grown in estrogen-supplemented mice. These data demonstrate that growth factors from estrogen-independent MDA-231 cells are not capable of replacing estrogen for growth stimulation of MCF-7 cells. Either estrogen-stimulated growth of MCF-7 cells requires other secreted factors not supplied by MDA-231 cells, or it involves a different mechanism.