Truncated RAR beta isoform enhances proliferation and retinoid resistance.
We previously reported the existence of a truncated isoform of the retinoic acid receptor beta, termed beta prime. Beta prime lacks the N-terminal domains of beta 2 and beta 4, including the DNA-binding domain. However, beta prime is able to heterodimerize and interact with transcription cofactors. To determine the effects of different retinoic acid receptor isoforms on cell proliferation and apoptosis, we transduced retinoid sensitive (MCF7) and retinoid-resistant (MDA-MB-231) cells with retinoic acid receptor beta 2, beta 4, or beta prime. Expression of the truncated beta prime isoform induces resistance to retinoic acid treatment in retinoid sensitive MCF7 cells. In both retinoid sensitive and resistant cells, expression of full-length beta 2 and beta 4 isoforms results in elevated sensitivity to retinoic acid treatment and caspase-independent cell death. Cell death in beta 4 transduced MDA-MB-231 cells was accompanied by metaphase chromosome decondensation and breakage suggestive of mitotic catastrophe. Our results provide evidence that: (a) the truncated form of the retinoic acid receptor beta induces retinoid resistance rather than sensitivity; and (b) alternative pathways of cell death are mediated by different isoforms in breast cancer cells.
Swift
Mari E
ME
Department of Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA.
Wallden
Brett
B
Wayner
Elizabeth A
EA
Swisshelm
Karen
K
D000970:Antineoplastic Agents / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005822:Genetic Vectors; D006801:Humans; D008938:Mitosis / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000378:metabolism*
D000970:Antineoplastic Agents; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D014212:Tretinoin