Retinoic acid receptor beta (RARbeta), and in particular RAR-beta2, RARbeta2 is a candidate tumor suppressor for human mammary gland tissue. RARbeta expression at the mRNA and protein level, in contrast to RARalpha and RARgamma, declines or is lost during breast tumor progression. Transcriptional and protein analysis suggests that the mechanism for this down-regulation or loss of expression is multi-factorial and includes transcriptional, post-transcriptional, and potential post-translational modifications. Breast cancer cells may exploit one or more of these regulatory controls of the RARbeta function in order to inhibit normal cellular functions. We wish to test the hypothesis that the RARbeta2 isoform is a tumor suppressor protein and that the recently identified human RARbeta4 isoform has the property of a dominant-negative transcription factor. We intend to characterize the critical regulatory mechanisms of RARbeta gene expression and function in normal human mammary epithelial cells (HMECs) and malignant breast carcinoma cells. We will characterize RARbeta transcripts and protein products as well as and the intracellular location of the proteins. We will introduce the truncated RARbeta4 transcripts, detected in breast cancer nuclei, into normal cells to study the biological consequences of nuclear localization. In order to test the hypothesis that differential levels, as well as aberrant subcellular localization, of RARbeta isoforms is a characteristic of primary breast cancers, we will utilize immunocytochemical (ICC) detection of RARbeta proteins against a panel of well-characterized breast cancer specimens. In order to determine transcriptional components necessary for repression of RARbeta and subsequent gene action in breast cancer cells, we will identify and characterize components of the transcriptional machinery influencing RARbeta2 transcription in breast tumor cells. These studies will provide the cytological and molecular basis for enhancing potential novel retinoid-directed therapies for human breast carcinoma as well as the basis for RARbeta as a diagnostic or prognostic tool.
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