title: 3, 3'5 Triiodo L thyronine induces apoptosis in human breast cancer MCF-7 cells, repressing SMP30 expression through negative thyroid response elements.
abstract: BACKGROUND
  Thyroid hormones regulate cell proliferation, differentiation as well as apoptosis. However molecular mechanism underlying apoptosis as a result of thyroid hormone signaling is poorly understood. The antiapoptotic role of Senescence Marker Protein-30 (SMP30) has been characterized in response to varieties of stimuli as well as in knock out model. Our earlier data suggest that thyroid hormone 3, 3'5 Triiodo L Thyronine (T(3)), represses SMP30 in rat liver.
  
  
  RESULTS
  In highly metastatic MCF-7, human breast cancer cell line T3 treatment repressed SMP30 expression leading to enhanced apoptosis. Analysis by flow cytometry and other techniques revealed that overexpression and silencing of SMP30 in MCF-7 resulted in decelerated and accelerated apoptosis respectively. In order to identify the cis-acting elements involved in this regulation, we have analyzed hormone responsiveness of transiently transfected hSMP30 promoter deletion reporter vectors in MCF-7 cells. As opposed to the expected epigenetic outcome, thyroid hormone down regulated hSMP30 promoter activity despite enhanced recruitment of acetylated H3 on thyroid response elements (TREs). From the stand point of established epigenetic concept we have categorised these two TREs as negative response elements. Our attempt of siRNA mediated silencing of TRβ, reduced the fold of repression of SMP30 gene expression. In presence of thyroid hormone, Trichostatin- A (TSA), which is a Histone deacetylase (HDAC) inhibitor further inhibited SMP30 promoter activity. The above findings are in support of categorisation of both the thyroid response element as negative response elements as usually TSA should have reversed the repressions.
  
  
  CONCLUSIONS
  This is the first report of novel mechanistic insights into the remarkable downregulation of SMP30 gene expression by thyroid hormone which in turn induces apoptosis in MCF-7 human breast cancer cells. We believe that our study represents a good ground for future effort to develop new therapeutic approaches to challenge the progression of breast cancer.
authors.affiliation: Cancer Biology Lab, Department of Gene Function and Regulation, Institute of Life Sciences, Chandrasekharpur, Bhubaneswar, India.
authors.forename: Pranati
authors.initials: P
authors.lastname: Sar
authors.forename: Rosalima
authors.initials: R
authors.lastname: Peter
authors.forename: Bandita
authors.initials: B
authors.lastname: Rath
authors.forename: Alok
authors.initials: A
authors.lastname: Das Mohapatra
authors.forename: Sandip K
authors.initials: SK
authors.lastname: Mishra
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D057809:HEK293 Cells; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic / Q000235:genetics; D020218:Response Elements / Q000235:genetics*; D020845:Selective Estrogen Receptor Modulators / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism*; D037042:Thyroid Hormone Receptors beta / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D014285:Triiodothyronine, Reverse / Q000494:pharmacology*
chemical_list: D002135:Calcium-Binding Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D047908:Intracellular Signaling Peptides and Proteins; C513323:RGN protein, human; D020845:Selective Estrogen Receptor Modulators; D037042:Thyroid Hormone Receptors beta; C012589:trichostatin A; D014285:Triiodothyronine, Reverse; D051548:Histone Acetyltransferases