With more than 250 scientific citations, Oncomine has become an industry standard for cancer researchers. This series features some of the latest scientific publications and how these scientists used Oncomine in various and novel ways for their research.

03 NOV 2009
KLF4 suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ERalpha¹.

In a recent publication (Oncogene (2009) 28, 2894–2902), scientists at the University of Tsukuba used Oncomine to demonstrate that KLF4 inhibits ERalpha, suppressing estrogen-dependent breast cancer growth.

The discovery included elucidation of a novel molecular network involving tumor protein p53 (TP53), Kruppel-like factor 4 (KLF4) and estrogen receptor (ER). The research team used Oncomine to show that KLF4 expression is downregulated in primary human breast tumors compared to normal breast, but within breast cancer samples, is positively correlated with ER+ breast cancers.

This analysis directed them to further investigate the role of KLF4 in breast cancer in the laboratory. They first performed a siRNA knockdown of KLF4 in the ER+ breast cancer cell line MCF-7 and showed a significant increase in cell growth, but only in the presence of estrogen.

Next, they performed coimmunoprecipitation experiments and found KLF4 bound to the DNA binding region of ER, which reduced the binding of ER to it’s promoter regions - effectively reducing the expression of ER target genes involved in cell growth and apoptosis.

Overall, authors present a model in which normally, in the presence of estrogen, ERalpha binds to Estrogen Response Elements (ERE) to activate estrogen-responsive oncogenes and drive breast cancer proliferation (Figure 1A). In contrast, the activation of TP53 by cellular stress signals activates KLF4, which binds to the DNA-binding region of ERalpha, preventing the downstream cascade of effects leading to breast cancer proliferation (Figure 1B).

Figure 1A: Breast cancer proliferation

Figure 1B: Cellular stress signals activates KLF4

Figure 1C: KLF4 repressing TP53 expression

Finally, these study authors suggest that in other contexts KLF4 acts as an oncogene, for example by repressing TP53 expression (Figure 1C), and may be an important molecular target for future therapies.

Figure 2: Oncomine Gene Summary across 500+ studies reveals a number of significant results of under-expression of KLF4 mRNA in breast cancers relative to normal breast, mutation subtype and grade subtype supporting the hypothesis of KLF4 as a tumor suppressor (Figs 2-4).

Figure 3: Several datasets show KLF4 to be the most significant under-expressed gene in cancer vs. normal analyses. This is shown in the Richardson Breast study within ductal breast carcinoma relative to normal breast. KLF4 is also highly ranked with significant P-values in several other independent datasets further validating this finding.

Figure 4: Oncomine analysis reveals decreasing expression of KLF4 mRNA at higher grades in the Ivshina study reflecting the loss of the tumor suppressor activity of KLF4 proposed by the research team. Similar findings were seen in several other pathology grade analyses within independent studies in Oncomine.

Figure 5: Higher expression of KLF4 was seen in ER+ breast cancer in two independent studies leading the research team to investigate the relationship between ER and KLF4.

Figure 6: Additional Oncomine analysis, beyond what the authors performed reveals decreased expression of KLF4 in reflecting the activation of KLF4 by TP53. That is, KLF4 is significantly under-expressed when the inactivating TP53 mutation is present, supporting the activation of KLF4 by TP53 and deregulation in breast cancer.

¹ KLF4 suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ERalpha.
Akaogi K, Nakajima Y, Ito I, Kawasaki S, Oie SH, Murayama A, Kimura K, Yanagisawa J.
Oncogene. 2009 Jun 8.

Oncomine 4.2.3 | Data (September 2009)