Date of Award

12-2001

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Dr. Hildegard M. Schuller

Committee Members

Sharon M. Patton, Michael F. McEntee, John L. Bell

Abstract

During the late stages of breast cancer progression, breast cancer cell growth switches from steroid hormone to growth factor dependence, and it is assumed that invasive breast cancers are growth factor receptor positive and estrogen hormone resistant. The cellular arachidonic acid (AA) pathway is upregulated in a variety of cancer types, and it may play an important role in the growth regulation of breast cancer cells.

Recent evidence suggests that beta-adrenergic receptors (β-ARs) are expressed in some estrogen receptor (ER) negative breast cancers and that beta agonists not only can trigger AA release via the activation of cytosolic PLA2 or MAPK but also stimulate DNA synthesis in ER (-) breast cancers. AA is metabolized to prostaglandins and leukotrienes by cyclooxygenases (COX-1, 2) and 5-lipoxygenase (5-LOX), respectively. COX-1 is constitutively expressed and required for the homeostatic function, whereas COX-2 is overexpressed during pathological conditions and cancer. It is well documented that COX-2 and 5-LOX are overexpressed in ER (-) breast cancers. Additionally, in many cell types there is a link between G-protein inwardly rectifying potassium channel 1 (GIRK1) and beta-adrenergic receptor pathways. A recent report has demonstrated overexpression of GIRK1 in metastatic breast carcinomas.

Using thymidine incorporation assays, this study shows that antagonists of β-AR, COX, 5-LOX or potassium channels in vitro decreased cell proliferation in both ER (-)

and (+) breast cancer cell lines. The general β-blocker propranolol was more effective than the selective β2-antagonist ICI 118,551 or the selective β1-antagonist atenolol. ER (+) cell lines generally were more responsive to the β1-antagonist atenolol whereas ER (- ) cell lines were more responsive to the β2-antagonists ICI 118,551. The β-1/ 2- agonist isoproterenol significantly increased DNA synthesis in only ER (-) cell lines. The reduction in DNA synthesis caused by the 5-LOX inhibitor MK-886 and non-specific LOX inhibitor NDGA was significantly higher in ER (-) cell lines than in ER (+) cell lines. The COX 1/2 inhibitor aspirin and the specific COX-2 inhibitor meloxicam reduced DNA synthesis in both cell lines. The potassium (K+) channel blocker quinidine inhibited DNA synthesis in both cell lines, and the ER (-) cell line MDA-MB-453 was more sensitive to this effect. RT-PCR experiments showed that the ER (-) cell line MDAMB- 453 expressed mRNA for the GIRK1 channel. In summary, our study suggests a link among beta-adrenergic receptor, potassium channel and AA cascade.

The observed ability of COX inhibitors, 5-LOX inhibitors, β-adrenergic blockers and K+ channel blockers to suppress the growth and proliferation of the a subset of human breast cancer cells lines is an important finding that provides the basis for the exploration of such agents in the clinical management and prevention of breast cancer. Because these inhibitors are already widely used for the treatment of various diseases they can immediately be used in clinical trials with breast cancer patients. In particular the β-ARs represent a promising new target for the development of new drug candidates with potential application in the clinical fields because a wealth of information is already available on the biochemical and molecular events underlying signaling by these receptors.

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