Progress 10/01/99 to 09/30/04
Outputs
My research program is centered on elucidating mechanisms of vitamin A metabolism and homeostasis and understanding the role of these processes in diseases including cancer. During the reporting period, we continued our studies comparing metabolic characteristics between normal mammary and breast cancer cells. These studies demonstrated that: a) normal mammary cells are growth inhibited to a greater extent by vitamin A (retinol) than breast cancer cells and that this growth inhibition is a function of the extent of metabolic conversion of retinol into retinoic acid; b) the relative ability to generate and respond to retinoic acid decreases in cells representative of more advanced stages of breast cancer; c) there are differences in the levels of transcripts encoding proteins involved in vitamin A transport, metabolism and signal transduction between normal and breast cancer cells. These findings indicate that alterations in vitamin A (retinoid) metabolic capacity are
correlated with breast cancer progression and that this likely affects the neoplastic behavior of breast cancer cells. In complementary studies, we have identified a new enzyme involved in retinol metabolism in epithelial cells. While at present it is too early to establish a link between this new enzyme and its possible role in cancer or other conditions affecting epithelial tissues. This project was terminated at the end of June 2002.
Impacts
Vitamin A, including its naturally occurring and synthetic analogs, exhibits a variety of benefits to human health including anti-cancer effects. In aggregate, our findings provide valuable insight into the molecular mechanisms underlying vitamin A metabolism and homeostasis, which will be built upon to better understand the role of vitamin A in specific diseases. As such, our findings have ramifications for both cancer diagnosis and treatment.
Publications
- No publications reported this period
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Progress 01/01/01 to 12/31/01
Outputs
My research program is centered on elucidating mechanisms of vitamin A metabolism and homeostasis and understanding the role of these processes in diseases including cancer. In the past year, we continued our studies comparing metabolic characteristics between normal mammary and breast cancer cells. These studies demonstrated that: a) normal mammary cells are growth inhibited to a greater extent by vitamin A (retinol) than breast cancer cells and that this growth inhibition is a function of the extent of metabolic conversion of retinol into retinoic acid; b) the relative ability to generate and respond to retinoic acid decreases in cells representative of more advanced stages of breast cancer; c) there are differences in the levels of transcripts encoding proteins involved in vitamin A transport, metabolism and signal transduction between normal and breast cancer cells. These findings indicate that alterations in vitamin A (retinoid) metabolic capacity are correlated
with breast cancer progression and that this likely affects the neoplastic behavior of breast cancer cells. In complementary studies, we have identified a new enzyme involved in retinol metabolism in epithelial cells. While at present it is too early to establish a link between this new enzyme and its possible role in cancer or other conditions affecting epithelial tissues, understanding the role of this enzyme in these processes is an avenue of future research. Another avenue of our research program is involved in understanding the molecular signals and mechanisms regulating the systemic transport protein for retinol, RBP. In the past year, we have shown that reduced zinc status enhances the expression of this transport protein. This observation indicates that the status of both the nutrients zinc and vitamin A are interrelated and provides mechanistic insight into how zinc may affect vitamin A utilization. All of this work will be continued and expanded upon in the upcoming year.
Impacts
Vitamin A, including its naturally occurring and synthetic analogs, exhibits a variety of benefits to human health including anti-cancer effects. In aggregate, our findings provide valuable insight into the molecular mechanisms underlying vitamin A metabolism and homeostasis, which will be built upon to better understand the role of vitamin A in specific diseases. As such, our findings have ramifications for cancer diagnosis and treatment.
Publications
- Hayden, L.J., Hawk, S.N. and Satre, M.A. (2001) The metabolic conversion of retinol to retinoic acid mediates the growth inhibition of human mammary epithelial cells. Journal of Cell Physiology 186:437-447.
- Satre, M.A., Jessen, K.A., Clegg, M.S., and Keen, C.L. (2001)Retinol-binding protein expression is induced in HepG2 cells by zinc deficiency. FEBS Letters 491:266-271.
- Motomura, K., Ohata, M., Satre, M.A. and Tsukamoto, H. (2001) Destabilization of TNF-alpha mRNA by retinoic acid in hepatic macrophages: implications for alcoholic liver disease. American Journal of Physiology, Endocrinology and Metabolism 281:E420429.
- Soref, C.M., Di, Y.P., Hayden, L.J., Zhao, Y.H., Satre, M.A. and Wu, R. (2001) Characterization of a novel airway epithelial cell-specific short chain alcohol dehydrogenase/reductase gene whose expression is up-regulated by retinoids and is involved in the metabolism of retinol. Journal of Biological Chemistry 276:24194-24202.
- Hayden, L.J., Hawk, S.N. and Satre, M.A. (2001) Alterations in cellular retinol metabolism contributing to differential retinoid responsiveness of normal mammary epithelial cells versus breast cancer cells. Breast Cancer Research and Treatment (in press).
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Progress 01/01/00 to 12/31/00
Outputs
My research program is centered on elucidating mechanisms of metabolism and homeostasis of vitamin A and related compounds (retinoids), and the role of these processes in diseases including cancer. In the past year, we have continued our comparative studies examining retinoid metabolism characteristics between normal mammary versus breast cancer cells and have found that: a) normal mammary cells exhibit greater uptake and metabolic generation of active (gene-regulatory, "anti-cancer") metabolites compared to breast cancer cells, and b) that the relative ability to generate and respond to these metabolites decreases in cells representative of more advanced stages of the disease; c) there are differences in the levels of transcripts encoding proteins involved in vitamin A transport, metabolism and signal transduction between normal and cancer cells; d) catabolic breakdown of active vitamin A metabolites is accelerated in cancer-derived versus normal cells. Another
avenue of our research program is involved in understanding the molecular signals and mechanisms regulating the systemic transport protein for vitamin A , RBP. In the past year, we have demonstrated that cyclic AMP and specific retinoids induce murine RBP expression. Our ongoing work seeks to understand the molecular mechanisms underlying RBP regulation. All of the above work will be continued and expanded upon in the upcoming year.
Impacts
Vitamin A, including its naturally occuring and synthetic analogs, exhibits a variety of benefits to human health including anti-cancer properties. Our research seeks to understand how these compounds are transported and metabolized by normal and cancerous cells. Results from these studies may provide valuable information regarding the progressive, metabolic changes in breast (and other) cancer and in so doing provide knowledge with diagnositic and therapeutic applications.
Publications
- JESSEN, K.A. and SATRE, M.A. 2000. Mouse retinol binding protein gene: cloning, expression and regulation by retinoic acid. Molecular and Cellular Biochemistry 211:85-94
- HAYDEN, L.J., HAWK, S.N., SIH, T.R. and SATRE, M.A. 2000 (in press) Metabolic conversion of retinol to retinoic acid mediates the biological responsiveness of human mammary epithelial cells to retinol. Journal of Cellular Physiology
- SATRE, M.A., JESSEN, K.A., CLEGG, M.S. and KEEN, C.L. 2000. (submitted/under review). Retinol binding protein expression is induced in HepG2 cells by zinc deficiency.
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Progress 01/01/99 to 12/31/99
Outputs
My research program is centered on elucidating mechanisms of vitamin A metabolism and homeostatis and understanding the role of these processes in diseaes including cancer. In the past year, we have undertaken comparative studies examing metabolic characteristics between normal mammary versus breast cancer cells. These studies demonstrated that: a) normal mammary cells are growth inhibited to a greater extent by vitamin A (retinol) than breast cancer cells; b) that this growth inhibition is a function of the extent of metabolic conversion of retinol into retinoic acid; c) that the relative ability to generate and respond to retinoic acid decreases in cells representative of more advanced stages of breast cancer; and d) there are differences in the levels of transcripts encoding proteins involved in vitamin A transport, metabolism and signal transduction between normal and breast cancer cells. Another avenue of our research program is involved in understanding the
molecular signals and mechanisms regulating the systemic transport protein for retinol, RBP. In the past year, we have shown that cyclic AMP and specific retinoids induce murine RBP expression. Initial characterization of the upstream regulatory regions of the mouse RBP gene indicate specific regions that mediate this regulation. In aggregate, this work will provide valuable information on the molecular mechanisms underlying vitamin A metabolism and homeostatis, which will be built upon to better understand the role of vitamin A in specific diseases. All of the above work will be continued and expanded upon in the coming year.
Impacts
(N/A)
Publications
- JESSEN, K.A. and SATRE, M.A., 2000. The mouse retinol binding protein gene: cloning, tissue expression and regulation by retinoic acid. (Submitted/under review).
- JESSEN, K.A. and SATRE, M.A., 2000. Transcriptional regulation of RBP by cyclic AMP. (Submitted/under review).
- HAYDEN, L.M. and SATRE, M.A., 2000. Retinol-mediated growth inhibition of normal human mammary epithelial cells is a function of the metabolic generation of retinoic acid. (Submitted/under review).
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