Breast carcinomas originate in epithelial cells; however, the growth and progression of these tumors is intimately related to the transformed epithelial cell's microenvironment. Steroidal sex hormones modulate the growth and differentiation of breast epithelial cells, and tumor progression is frequently associated with loss of hormone responsiveness. Since hormonal intervention remains a key component of treatment for both breast and prostate cancer patients, it is essential to determine the mechanisms underlying tumor progression from hormone responsive to hormone insensitive states. We have recently demonstrated that a key component of androgen independent growth control in prostate carcinoma cells is the acquisition of alternate growth regulatory pathways. We believe analogous growth factor/receptor circuits may become established in transformed breast epithelial cells during tumor progression. In this regard IL-6 has been reported to inhibit the in vitro proliferation of several human breast carcinoma cell lines. Furthermore, we have preliminary data to suggest that steroid sensitive breast epithelial cells are growth inhibited by IL-6, whereas steroid insensitive epithelial cells, in contrast, are not. We have, therefore, hypothesized that human breast carcinoma cells undergo a transition from IL-6 functioning as a paracrine inhibitor to an autocrine stimulator during the progression of tumor cells from a steroid sensitive to a steroid insensitive state. We further hypothesize that there is a functional dependence on steroid receptor expression that is correlated with IL-6 growth inhibition of breast epithelial cells. We have also demonstrated that a novel truncated form of the IL-6 receptor can dramatically potentiate IL-6 mediated breast carcinoma cell growth inhibition, in vitro, and in this application we propose to test the utility of this potent growth inhibitor in blocking breast carcinoma cell growth in vivo.
| Cleary, Margot P; Phillips, Frederick C; Getzin, Susan C et al. (2003) Genetically obese MMTV-TGF-alpha/Lep(ob)Lep(ob) female mice do not develop mammary tumors. Breast Cancer Res Treat 77:205-15 |
| Cleary, M P; Maihle, N J (1997) The role of body mass index in the relative risk of developing premenopausal versus postmenopausal breast cancer. Proc Soc Exp Biol Med 216:28-43 |
