ABSTRACT: Expression of MYB is essential for the proliferation of ER+ve breast cancer cells and breast cancer development in mouse models. Transcription of this oncogene is tightly regulated by a transcriptional pausing mechanism where the pausing site is located within the first intron, about 1.7kb downstream from the transcription start site. We recently showed that treatment with the CDK9 inhibitors such as Flavopiridol, DRB selectively downregulates MYB transcription when cells were treated for 3-4h at low concentrations. Our data also indicated that ERα-P-TEFb (heterodimer of CyclinT1 and CDK9) complex is recruited to the pausing site in the presence of Estrogen. P-TEFb in turn phosphorylates the C-terminal domain Ser-2 residue of RNA PolII to allow transcription to resume (Mitra, 2012). We have now further investigated the effect of inhibitors of transcriptional elongation, in particular CDK9 inhibitors, on the growth and survival of ER+ve breast cancer cells. We found that ER+ve breast cancer cells expressing MYB (ER+veMYB+ve) were five- to six-fold more sensitive to CDK9 inhibitors, such as Flavopiridol or AT7519, than ER-veMYB-ve breast cancer cells. Moreover, when treated with low concentrations of Flavopiridol or AT7519 for 72h, ER+ve MYB+ve cells were undergone retarded cell proliferation, G2/M check point accumulation and early apoptosis. These effects were not observed in ER-veMYB-ve cells until much higher concentrations were used. In parallel with MYB, we also found a significant downregulation of MYB target genes CyclinB1 and CyclinE1 in the presence of drugs in ER+ve MYB+ve cells. On the other hand, expression of CyclinD1, a MYB non target gene, was not significantly affected. Importantly, the effect of either of these drugs can be overcome by stable ectopic expression of MYB in on ER+veMYB+ve cell line. Therefore, we conclude that the extra sensitivity of ER+veMYB+ve cells to the CDK9 inhibitors due to selective downregulation of MYB by those drugs provides an opportunity to use those inhibitors to control the progression of this subtype of breast cancer.