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.
","abstract_html":"<p>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.</p> <p>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.</p> <p>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<sup>-6</sup>M 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<sup>-4</sup>M 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<sup>-6</sup> M. In contrast, ER- cells (MCF-lOA, Hs578t) showed no RSV-related inerease in growth or changes in IGF-II/proIGF-II expression.</p> <p>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<sup>-4</sup>M)-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.</p> <p>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.</p>","abstract_has_math":false,"creators":["Vyas, Sharda Kalla"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation","degree_discipline":"Anatomy","degree_department":null,"school":null,"contributors":["Daisy D. De Leon","Carlos A. Casiano","Subburaman Mohan","Kerby Oberg","Kenneth Wright"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2005,"date_issued":"2005-06-01T07:00:00Z","date_published":"2005-06-01T07:00:00Z","updated_at":"2026-07-24T02:54:10Z","subjects":["Anatomy","Breast Neoplasms; Phytoestrogens -- adverse effects; Estrogens; Insulin-Like Growth Factor II; Cathepsin D."],"languages":["English"],"rights":["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."],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://scholarsrepository.llu.edu/etd/1221","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Daisy D. De Leon","Carlos A. Casiano","Subburaman Mohan","Kerby Oberg","Kenneth Wright"]},{"key":"dc:creator","label":"Author","values":["Vyas, Sharda Kalla"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"thesis:degree_discipline","label":"Discipline","values":["Anatomy"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Anatomy","Breast Neoplasms; Phytoestrogens -- adverse effects; Estrogens; Insulin-Like Growth Factor II; Cathepsin D."]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["English"]},{"key":"dc:rights","label":"Dc Rights","values":["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."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://scholarsrepository.llu.edu/etd/1221"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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.
"]},{"key":"dc:title","label":"Title","values":["Resveratrol Regulates IGF- II and Cathepsin D in Breast Cancer Cells"]}]}],"canonical_facts":{"dc:contributor":["Daisy D. De Leon","Carlos A. Casiano","Subburaman Mohan","Kerby Oberg","Kenneth Wright"],"dc:creator":["Vyas, Sharda Kalla"],"dc:description.abstract":["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.
"],"dc:identifier":["https://scholarsrepository.llu.edu/etd/1221"],"dc:language":["English"],"dc:rights":["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."],"dc:subject":["Anatomy","Breast Neoplasms; Phytoestrogens -- adverse effects; Estrogens; Insulin-Like Growth Factor II; Cathepsin D."],"dc:title":["Resveratrol Regulates IGF- II and Cathepsin D in Breast Cancer Cells"],"thesis:degree_discipline":["Anatomy"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T02:54:10Z"}