Growth Factor Secretion in Human Breast Carcinoma

Abstract

Hormonal influences on cancer cell proliferation have received much attention with the proposal of autocrine or self-stimulating polypeptide growth factors. The growth of breast cancer is known to be under endocrine control by steroid .hormones. Estrogen stimulates the proliferation of human breast cancer cell lines in vitro and in vivo. Polypeptide growth factors may be common mediators of growth control for both estrogen-regulated and autonomous breast cancer cells. Estrogens induce a large number of enzymes involved in nucleic acid synthesis, the progesterone receptor, plasminogen activator, collagenolytic enzymes, and the laminin receptor. The effect of these proteins includes growth regulation and other activities thought to mediate metastatic events. In addition to the above proteins, growth factors are known to be stimulated by estrogen. It has been observed that the initial growth rate of a hormone-dependent cell line MCF-7 in vitro is proportional to the number of cells plated. This is consistent with the production of autostimulatory growth factors by the MCF-7 cells. More direct studies using estrogen-free extracts of conditioned medium (CM) harvested from MCF-7 cells treated with 17-/%estradiol (E 2) shows that CME 2 stimulated increases in the number of MCF-7 cells. E 2 is an absolute tumor growth requirement for MCF-7 cells. In addition, CME 2 given by continous infusion in vivo to the nude mouse was also capable of stimulating MCF-7 tumorigenesis in the absence of E2. These data support the hypothesis that cultured human breast cancer cells under estrogenic stimulation release a tumor-promoting factor(s) which can act in vitro or in vivo after release into the general circulation of the nude mouse. It has been shown that CM from MCF-7 and other breast cancer cell lines secrete growth-stimulatory activities for both MCF-7 cells and a transforming growth activity for anchorage-independent growth of rodent fibroblasts. Isolation of one of these activities reveals that it coincides with the principal competitor of EGF receptor binding activity. This activity is related to transforming growth factor alpha (TGFe). It has also been shown that this activity is estrogen regulated at the protein and mRNA level. Anti-EGF receptor antibodies decrease the growth of breast cancer cells in culture. It may be that interruption of this loop will be clinically applicable in the future in breast cancer treatment. It has also been shown that insulin-like growth factor-1 (IGF-1) is an autostimulatory mitogen for breast cancer. Breast cancer cells have been shown to secrete a TGF-/~ related activity. TFG-/~ is growth inhibitory for many epithelial and breast cancer cell lines. TGF-/~ is inhibited in MCF-7 cells by treatment with E 2 and conversely stimulated by antiestrogens. Interestingly, TGF-fl inhibits the growth of hormoneindependent cell lines or cells that lack estrogen receptor:. Breast cancers exist as mixtures of estrogen receptor positive and negative tumor cells. Since breast