The transcriptional modulator BCL6 as a molecular target for breast cancer therapy

Abstract

Inappropriate expression or activation of transcription factors can drive patterns of gene expression leading to the malignant behavior of breast cancer cells. We have found that the transcriptional repressor BCL6 is highly expressed in breast cancer cell lines, and its locus is amplified in about half of primary breast cancers. To understand how BCL6 regulates gene expression in breast cancer cells, we utilized ChIP-seq to identify the BCL6 binding sites on a genomic scale. This revealed that BCL6 regulates a unique cohort of genes in breast cancer cell lines compared to B cell lymphomas. Furthermore, BCL6 expression promotes the survival of breast cancer cells, and targeting BCL6 with a peptidomimetic inhibitor leads to apoptosis of these cells. Finally, combining a BCL6 inhibitor and a STAT3 inhibitor provided enhanced cell killing in triple negative breast cancer cell lines, suggesting that combination therapy may be particularly useful. Thus, targeting BCL6 alone or in conjunction with other signaling pathways may be a useful therapeutic strategy for treating breast cancer.

B-cell lymphoma 6 promotes proliferation and survival of trophoblastic cells

“…16 Moreover, it is also found in many tissues such as skeletal muscle, breast and prostate. 17,18 In support of this observation, recent studies have uncovered that deregulation of BCL6 is involved in breast cancer development by blocking differentiation of breast epithelia cells, [18][19][20] suggesting that BCL6 exerts similar function in non-haematopoietic cells as well.…”

“…18,19 A recent study has further revealed that BCL6 expression promotes proliferation and survival of breast cancer cells and inhibiting BCL6 leads to apoptosis of these cells by targeting a cohort of genes. 20 It has been reported that proliferation and apoptosis of trophoblasts are deregulated in preeclamptic placentas. [42][43][44] Interestingly, an increase in the mRNA of BCL6 in preeclamptic placentas has been observed independently by several groups, [21][22][23]26 yet its roles in the development of preeclampsia remain to be clarified.…”

BCL6 induces EMT by promoting the ZEB1-mediated transcription repression of E-cadherin in breast cancer cells

“…However, we did not detect any binding of BCL6 to the E-cadherin promoter (data not shown). A number of studies demonstrate that a variety of transcriptional repressors including Snail, Twist, Slug, deltaEF1/ZEB1, SIP1/ZEB2 and CtBP2 can bind to the E-cadherin promoter and inhibit the gene transcription [5][6][7][8][9][10][11][12]. We therefore screened which transcription repressor mediated the BCL6-repressed E-cadherin expression with siRNA assay.…”

“…By binding to specific DNA sequences, BCL6 controls the transcriptional expression of target genes involved in the pathogenesis of B-cell lymphomas or breast cancers [6,7]. Once it binds to the target DNA sequences, BCL6 recruits corepressor SMRT, NCOR or BCOR through its BTB domain and regulates cellular proliferation and survival [8].…”

“…Moreover, the expression level of BCL6 positively associates with poor survival of breast cancer patients [5]. Therefore, BCL6 has been found to have a potential acting as a therapeutic target for breast cancer [6]. However, the mechanism of BCL6 regulating the development and progression of breast cancer remains to be clarified.…”