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.

LLU Discipline





Graduate School

First Advisor

Daisy D. De Leon

Second Advisor

Carlos A. Casiano

Third Advisor

Subburaman Mohan

Fourth Advisor

Kerby Oberg

Fifth Advisor

Kenneth Wright

Degree Name

Doctor of Philosophy (PhD)

Degree Level


Year Degree Awarded


Date (Title Page)




Library of Congress/MESH Subject Headings

Breast Neoplasms; Phytoestrogens -- adverse effects; Estrogens; Insulin-Like Growth Factor II; Cathepsin D.



Page Count

xii; 111

Digital Format


Digital Publisher

Loma Linda University Libraries

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This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.


Loma Linda University Electronic Theses and Dissertations

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Loma Linda University. Del E. Webb Memorial Library. University Archives

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