Resveratrol Regulates IGF- II and Cathepsin D in Breast Cancer Cells
Breast cancer is the most common type of cancer among women in the US. Phytoestrogen resveratrol (RS V) has been described as a potential ehemotherapeutic agent, but has been associated with breast cancer cell growth and cell death. RSV binds to estrogen receptors (ER) and functions as a mixed estrogen agonist/antagonist. The mechanism by which RSV regulates breast cancer growth is largely unknown, but it likely targets factors regulated by estrogens. Insulin-like growth factor II (IGF-II) and its precursor (proIGF-II) are estrogen-regulated mitogens that are over-expressed in breast carcinoma. Thus, I hypothesized that IGF-II/proIGF-II might mediate the biphasic effects of RSV on breast cancer cell growth. The hypothesis was tested by the following specific aims: (I) Determine RSV modulation of breast cancer cell growth in ER +/- cells; (2) Identify the effect of RSV on IGF-II/proIGF-II expression in breast cancer cells; (3) Determine whether IGFII/ proIGF-II mediates RSV effects on breast cancer cells; (4) Identify IGF-II/proIGF-II targets involved in breast cancer cell modulation - i.e. apoptotie genes and Cathepsin D (CD), an estrogen-regulated protein elevated in breast cancer. RSV displays a biphasic effect on cell growth and IGF-II expression in ER+ breast carcinoma cells. In ER+ cells (MCF-7, T47D), RSV at 10-6M induces a 2-fold increase in cell growth with an increase in proIGF-II expression (2.5 fold by Northern) and seeretion (2 fold by Western) 24 hr post-treatment. While RSV at 10-4M inhibited cell growth, deereased proIGF-II expression, and redueed proIGF-II secretion (by 50%, 50% and 30%, respectively). Furthermore, blocking antibody to the IGF-I receptor (mediator of IGF-II signal transduetion) completely inhibited the growth stimulatory effeet of RSV 10-6 M. In contrast, ER- cells (MCF-lOA, Hs578t) showed no RSV-related inerease in growth or changes in IGF-II/proIGF-II expression. Over-expression of IGF-II, either endogenous or exogenous via an expression plasmid, induced an increase in CD secretion (2 fold) irrespective of ER status. In addition, the RSV (10-4M)-induced down-regulation of IGF-II led to a decrease in the anti-apoptotic proteins Bcl-2 and survivin (2.5 and 2 fold respeetively) that could be reversed by exogenous proIGF-II (lOOng/ml) or by over-expression of a proIGF-II expression plasmid. In summary, these data demonstrate that RSV could increase the risk of breast cancer growth at low coneentration by increasing proIGF-II levels. Furthermore, these data suggest that IGF-II/proIGF-II manifests its effeets on breast cancer growth by inducing CD secretion and up-regulating the anti-apoptotie proteins Bel-2 and survivin.
Anatomy, Breast Neoplasms; Phytoestrogens -- adverse effects; Estrogens; Insulin-Like Growth Factor II; Cathepsin D.
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