Inhibition of estrogen-dependent breast cell responses with phenylacetate

Abstract

The aromatic fatty acid phenylacetate (PA) and its analogs have come under intense investigation due to their ability to cause the growth arrest of a variety of neoplasia, including human breast cancer. We have determined that PA and its halide derivative 4-chlorophenylacetate (4-CPA) showed marked antiproliferative activity on 3 of 6 human breast cancer cell lines tested. Interestingly, the 3 cell lines that were growth inhibited by PA and 4-CPA were estrogen receptor (ER) positive (T47-D, MCF-7 and ZR-75-1) whereas those that were little affected by these compounds were ER-negative (MDA-MB-157, MDA-MB-231 and SK-Br-3). Dose response studies indicated that 4-CPA inhibited the growth of the sensitive (ER؉) cell lines with a potency 3-4 times that of PA. These findings suggest that there is "crosstalk" between the PA and estrogen signaling pathways such that PA can directly inhibit estrogen-dependent events. This hypothesis was directly tested in vitro using ER؉ MCF-7 cells that were stably transfected with a luciferase reporter construct driven by the full length ( Key words: phenylacetate; breast cancer; estrogen; receptorBreast cancer is 1 of the most prevalent types of cancer observed in women, developing in approximately 1 of 9 women sometime during their lifetime. The etiology of this malignancy is known to involve a complex interplay of genetic, environmental, and hormonal factors that influence the physiological status of the host. 1,2 With regards to the latter factor, there is considerable data that implicate the involvement of steroid hormones, especially estrogen, in the development and progression of breast cancer. This fact has lead to the use of antiestrogens in the therapeutic intervention of this disease. To date, the clinical use of antiestrogens has been limited to compounds that inhibit estrogen signaling at the level of the estrogen receptor (ER) by competing with the ligand (i.e., estrogen) for receptor binding. 3 Although shown to be extremely useful, the clinical results are often unpredictable due to the complex functional activity of ERs liganded with different antiestrogen compounds or the ability of the receptors to undergo changes (mutations or otherwise) that can alter their functional characteristics or response to estrogen antagonists. 4 Thus, there is a need to develop therapeutic compounds that can inhibit the estrogen signaling pathway by mechanisms that may not depend upon competitive ligand binding to the ER.Aromatic fatty acids, of which phenylacetate (PA) is a prototype, constitute a new class of low toxicity drugs with demonstrated antitumor activity in experimental models and in humans. PA is a natural metabolite of phenylalanine that was originally described as a plant growth hormone. 5 Normally found in micromolar concentrations in human plasma, PA has a long clinical history as treatment for conditions associated with hyperammonemia such as in children with urea cycle disorders. 6,7 This clinical experience has indicated that millimolar blood serum levels can be achiev...

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XR5944: A potent inhibitor of estrogen receptors

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