Limits...
Regulation of anti-apoptotic signaling by Kruppel-like factors 4 and 5 mediates lapatinib resistance in breast cancer.

Farrugia MK, Sharma SB, Lin CC, McLaughlin SL, Vanderbilt DB, Ammer AG, Salkeni MA, Stoilov P, Agazie YM, Creighton CJ, Ruppert JM - Cell Death Dis (2015)

Bottom Line: Indicating cooperativity, greater effects were observed when both genes were depleted.KLF4/5-deficient cells had reduced basal mRNA and protein levels of the anti-apoptotic factors myeloid cell leukemia 1 (MCL1) and B-cell lymphoma-extra large (BCL-XL).These results identify KLF4 and KLF5 as cooperating protumorigenic factors and critical participants in resistance to lapatinib, furthering the rationale for combining anti-MCL1/BCL-XL inhibitors with conventional HER2-targeted therapies.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Biochemistry, West Virginia University Health Sciences Center, Morgantown, WV 26506, USA [2] Program in Cancer Cell Biology, West Virginia University, Morgantown, WV 26506, USA.

ABSTRACT
The Kruppel-like transcription factors (KLFs) 4 and 5 (KLF4/5) are coexpressed in mouse embryonic stem cells, where they function redundantly to maintain pluripotency. In mammary carcinoma, KLF4/5 can each impact the malignant phenotype, but potential linkages to drug resistance remain unclear. In primary human breast cancers, we observed a positive correlation between KLF4/5 transcript abundance, particularly in the human epidermal growth factor receptor 2 (HER2)-enriched subtype. Furthermore, KLF4/5 protein was rapidly upregulated in human breast cancer cells following treatment with the HER2/epidermal growth factor receptor inhibitor, lapatinib. In addition, we observed a positive correlation between these factors in the primary tumors of genetically engineered mouse models (GEMMs). In particular, the levels of both factors were enriched in the basal-like tumors of the C3(1) TAg (SV40 large T antigen transgenic mice under control of the C3(1)/prostatein promoter) GEMM. Using tumor cells derived from this model as well as human breast cancer cells, suppression of KLF4 and/or KLF5 sensitized HER2-overexpressing cells to lapatinib. Indicating cooperativity, greater effects were observed when both genes were depleted. KLF4/5-deficient cells had reduced basal mRNA and protein levels of the anti-apoptotic factors myeloid cell leukemia 1 (MCL1) and B-cell lymphoma-extra large (BCL-XL). Moreover, MCL1 was upregulated by lapatinib in a KLF4/5-dependent manner, and enforced expression of MCL1 in KLF4/5-deficient cells restored drug resistance. In addition, combined suppression of KLF4/5 in cultured tumor cells additively inhibited anchorage-independent growth, resistance to anoikis and tumor formation in immunocompromised mice. Consistent with their cooperative role in drug resistance and other malignant properties, KLF4/5 levels selectively stratified human HER2-enriched breast cancer by distant metastasis-free survival. These results identify KLF4 and KLF5 as cooperating protumorigenic factors and critical participants in resistance to lapatinib, furthering the rationale for combining anti-MCL1/BCL-XL inhibitors with conventional HER2-targeted therapies.

Show MeSH

Related in: MedlinePlus

Prognostic significance of KLF4 and KLF5 in human breast cancer. Kaplan–Meier analysis utilized a previously described breast cancer microarray database.40 Red (hi) and blue (lo) groups were defined using the median gene expression level within the tumors of breast cancer patients. A total of 364 luminal A, 175 luminal B, 239 HER2-enriched and 287 basal-like/claudin-low tumors were analyzed. (a) KLF4/5 were analyzed as single variables for all tumors combined. (b) KLF4/5 were analyzed as single variables within the basal-like/claudin-low and the HER2-enriched groups, as defined by PAM50 subtyping. (c) The outcome of patients harboring tumors with higher expression levels of both KLF4 and KLF5 (red, hi-hi) was compared with the outcome when tumors had lower expression levels of each factor (blue, lo-lo). For all curves, significance was determined using the log-rank (Mantel–Cox) test and P<0.05 was considered significant
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4385942&req=5

fig2: Prognostic significance of KLF4 and KLF5 in human breast cancer. Kaplan–Meier analysis utilized a previously described breast cancer microarray database.40 Red (hi) and blue (lo) groups were defined using the median gene expression level within the tumors of breast cancer patients. A total of 364 luminal A, 175 luminal B, 239 HER2-enriched and 287 basal-like/claudin-low tumors were analyzed. (a) KLF4/5 were analyzed as single variables for all tumors combined. (b) KLF4/5 were analyzed as single variables within the basal-like/claudin-low and the HER2-enriched groups, as defined by PAM50 subtyping. (c) The outcome of patients harboring tumors with higher expression levels of both KLF4 and KLF5 (red, hi-hi) was compared with the outcome when tumors had lower expression levels of each factor (blue, lo-lo). For all curves, significance was determined using the log-rank (Mantel–Cox) test and P<0.05 was considered significant

Mentions: Across all tumors, KLF4 levels showed no significant relationship with DMFS (Figure 2a). In contrast, elevated KLF5 was associated with shortened DMFS, consistent with prior observations (hazard ratio (HR), 1.3; 95% confidence interval (CI), 1.1–1.7; P=0.01; Figure 2a).11


Regulation of anti-apoptotic signaling by Kruppel-like factors 4 and 5 mediates lapatinib resistance in breast cancer.

Farrugia MK, Sharma SB, Lin CC, McLaughlin SL, Vanderbilt DB, Ammer AG, Salkeni MA, Stoilov P, Agazie YM, Creighton CJ, Ruppert JM - Cell Death Dis (2015)

Prognostic significance of KLF4 and KLF5 in human breast cancer. Kaplan–Meier analysis utilized a previously described breast cancer microarray database.40 Red (hi) and blue (lo) groups were defined using the median gene expression level within the tumors of breast cancer patients. A total of 364 luminal A, 175 luminal B, 239 HER2-enriched and 287 basal-like/claudin-low tumors were analyzed. (a) KLF4/5 were analyzed as single variables for all tumors combined. (b) KLF4/5 were analyzed as single variables within the basal-like/claudin-low and the HER2-enriched groups, as defined by PAM50 subtyping. (c) The outcome of patients harboring tumors with higher expression levels of both KLF4 and KLF5 (red, hi-hi) was compared with the outcome when tumors had lower expression levels of each factor (blue, lo-lo). For all curves, significance was determined using the log-rank (Mantel–Cox) test and P<0.05 was considered significant
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385942&req=5

fig2: Prognostic significance of KLF4 and KLF5 in human breast cancer. Kaplan–Meier analysis utilized a previously described breast cancer microarray database.40 Red (hi) and blue (lo) groups were defined using the median gene expression level within the tumors of breast cancer patients. A total of 364 luminal A, 175 luminal B, 239 HER2-enriched and 287 basal-like/claudin-low tumors were analyzed. (a) KLF4/5 were analyzed as single variables for all tumors combined. (b) KLF4/5 were analyzed as single variables within the basal-like/claudin-low and the HER2-enriched groups, as defined by PAM50 subtyping. (c) The outcome of patients harboring tumors with higher expression levels of both KLF4 and KLF5 (red, hi-hi) was compared with the outcome when tumors had lower expression levels of each factor (blue, lo-lo). For all curves, significance was determined using the log-rank (Mantel–Cox) test and P<0.05 was considered significant
Mentions: Across all tumors, KLF4 levels showed no significant relationship with DMFS (Figure 2a). In contrast, elevated KLF5 was associated with shortened DMFS, consistent with prior observations (hazard ratio (HR), 1.3; 95% confidence interval (CI), 1.1–1.7; P=0.01; Figure 2a).11

Bottom Line: Indicating cooperativity, greater effects were observed when both genes were depleted.KLF4/5-deficient cells had reduced basal mRNA and protein levels of the anti-apoptotic factors myeloid cell leukemia 1 (MCL1) and B-cell lymphoma-extra large (BCL-XL).These results identify KLF4 and KLF5 as cooperating protumorigenic factors and critical participants in resistance to lapatinib, furthering the rationale for combining anti-MCL1/BCL-XL inhibitors with conventional HER2-targeted therapies.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Biochemistry, West Virginia University Health Sciences Center, Morgantown, WV 26506, USA [2] Program in Cancer Cell Biology, West Virginia University, Morgantown, WV 26506, USA.

ABSTRACT
The Kruppel-like transcription factors (KLFs) 4 and 5 (KLF4/5) are coexpressed in mouse embryonic stem cells, where they function redundantly to maintain pluripotency. In mammary carcinoma, KLF4/5 can each impact the malignant phenotype, but potential linkages to drug resistance remain unclear. In primary human breast cancers, we observed a positive correlation between KLF4/5 transcript abundance, particularly in the human epidermal growth factor receptor 2 (HER2)-enriched subtype. Furthermore, KLF4/5 protein was rapidly upregulated in human breast cancer cells following treatment with the HER2/epidermal growth factor receptor inhibitor, lapatinib. In addition, we observed a positive correlation between these factors in the primary tumors of genetically engineered mouse models (GEMMs). In particular, the levels of both factors were enriched in the basal-like tumors of the C3(1) TAg (SV40 large T antigen transgenic mice under control of the C3(1)/prostatein promoter) GEMM. Using tumor cells derived from this model as well as human breast cancer cells, suppression of KLF4 and/or KLF5 sensitized HER2-overexpressing cells to lapatinib. Indicating cooperativity, greater effects were observed when both genes were depleted. KLF4/5-deficient cells had reduced basal mRNA and protein levels of the anti-apoptotic factors myeloid cell leukemia 1 (MCL1) and B-cell lymphoma-extra large (BCL-XL). Moreover, MCL1 was upregulated by lapatinib in a KLF4/5-dependent manner, and enforced expression of MCL1 in KLF4/5-deficient cells restored drug resistance. In addition, combined suppression of KLF4/5 in cultured tumor cells additively inhibited anchorage-independent growth, resistance to anoikis and tumor formation in immunocompromised mice. Consistent with their cooperative role in drug resistance and other malignant properties, KLF4/5 levels selectively stratified human HER2-enriched breast cancer by distant metastasis-free survival. These results identify KLF4 and KLF5 as cooperating protumorigenic factors and critical participants in resistance to lapatinib, furthering the rationale for combining anti-MCL1/BCL-XL inhibitors with conventional HER2-targeted therapies.

Show MeSH
Related in: MedlinePlus