All ETDs from UAB

Advisory Committee Chair

Robert W Hardy

Advisory Committee Members

Susan L Bellis

Lisa M Schwiebert

Gene P Siegal

Danny R Welch

Anne Woods

Document Type

Dissertation

Date of Award

2009

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

earate is an 18-carbon saturated fatty acid that is found in many foods in the western diet including beef and chocolate. Cell culture studies indicate stearate may have various anti-cancer properties including inhibition of cancer cell proliferation and invasion, morphological changes, and induction of apoptosis. Animal studies have found that dietary stearate delays tumor development and decreases tumor incidence. To date, many of the mechanisms underlying these processes are unclear. In this study, evidence is presented showing stearate induces morphological changes in breast cancer cells. Inhibition of de novo diacylglycerol (DAG) generation and subsequent protein kinase C (PKC) activation inhibits stearate-induced cell rounding. Further examination of the individual PKC isozymes with pharmacologic inhibitors indicates that PKC may be directly involved in stearate-induced cell rounding. Similar results were obtained with caspase-3 activity assays where stearate treatment appears to induce apoptosis of breast cancer cells in a manner dependent on DAG and PKC. Stearate induces apoptosis in a time and dose dependent manner through a pathway mediated by both the extrinsic and intrinsic cascades. In vivo, dietary stearate decreases primary tumor size in athymic nude mice injected in the mammary fat pad with MDA-MB-435 breast cancer cells. Stearate also inhibits metastasis to the lungs through a mechanism independent of primary tumor size. Future studies are necessary to elucidate the mechanisms underlying the dietary stearate-induced decrease in primary tumor size and inhibition of metastasis. Taken together, these results indicate stearate may be a potential preventative and/or adjuvant therapy for those at high risk for developing breast cancer.

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