Among the genes regulated by estrogen receptor (ER) are miRNAs that play a role in breast cancer signaling pathways. To determine whether miRNAs are involved in ER-positive breast cancer progression to hormone independence, we profiled the expression of 800 miRNAs in the estrogen-dependent human breast cancer cell line MCF7 and its estrogen-independent derivative MCF7:2A (MCF7:2A) using NanoString. We found 78 miRNAs differentially expressed between the two cell lines, including a cluster comprising let-7c, miR99a, and miR125b, which is encoded in an intron of the long noncoding RNA LINC00478. These miRNAs are ER targets in MCF7 cells, and nearby ER binding and their expression are significantly decreased in MCF7:2A cells. The expression of these miRNAs was interrogated in patient samples profiled in The Cancer Genome Atlas (TCGA). Among luminal tumors, these miRNAs are expressed at higher levels in luminal A versus B tumors. Although their expression is uniformly low in luminal B tumors, they are lost only in a subset of luminal A patients. Interestingly, this subset with low expression of these miRNAs had worse overall survival compared with luminal A patients with high expression. We confirmed that miR125b directly targets HER2 and that let-7c also regulates HER2 protein expression. In addition, HER2 protein expression and activity are negatively correlated with let-7c expression in TCGA. In summary, we identified an ER-regulated miRNA cluster that regulates HER2, is lost with progression to estrogen independence, and may serve as a biomarker of poor outcome in ER+ luminal A breast cancer patients. Cancer Res; 75(2); 1–10. ©2014 AACR.

Among the genes regulated by estrogen receptor (ER) are miRNAs that play a role in breast cancer signaling pathways. To determine whether miRNAs are involved in ER-positive breast cancer progression to hormone independence, we profiled the expression of 800 miRNAs in the estrogen-dependent human breast cancer cell line MCF7 and its estrogen-independent derivative MCF7:2A (MCF7:2A) using NanoString. We found 78 miRNAs differentially expressed between the two cell lines, including a cluster comprising let-7c, miR-99a, and miR-125b, which is encoded in an intron of the long non-coding RNA LINC00478. These miRNAs are ER targets in MCF7 cells, and nearby ER binding and their expression is significantly decreased in MCF7:2A cells. The expression of these miRNAs was interrogated in patient samples profiled in The Cancer Genome Atlas (TCGA). Among luminal tumors, these miRNAs are expressed at higher levels in luminal A vs. B tumors. While their expression is uniformly low in luminal B tumors, they are lost only in a subset of luminal A patients. Interestingly, this subset with low expression of these miRNAs had worse overall survival compared with luminal A patients with high expression. We confirmed that miR-125b directly targets HER2 and that let-7c also regulates HER2 protein expression. In addition, HER2 protein expression and activity is negatively correlated with let-7c expression in TCGA. In summary, we identified an ER-regulated miRNA cluster that regulates HER2, is lost with progression to estrogen independence, and may serve as a biomarker of poor outcome in ER+ luminal A breast cancer patients.

LASP1 is an actin-binding protein associated with actin assembly dynamics in cancer cells. Here, we report that LASP1 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) where it promotes invasion and metastasis. We found that LASP1 overexpression in PDAC cells was mediated by HIF1α through direct binding to a hypoxia response element in the LASP1 promoter. HIF1α stimulated LASP1 expression in PDAC cells in vitro and mouse tumor xenografts in vivo. Clinically, LASP1 overexpression in PDAC patient specimens was associated significantly with lymph node metastasis and overall survival. Overall, our results defined LASP1 as a direct target gene for HIF1α upregulation that is critical for metastatic progression of PDAC. Cancer Res; 75(1); 1–9. ©2014 AACR.

LASP1 is an actin-binding protein associated with actin assembly dynamics in cancer cells. Here we report that LASP1 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) where it promotes invasion and metastasis. We found that LASP1 overexpression in PDAC cells was mediated by HIF-1α through direct binding to a hypoxia response element in the LASP1 promoter. HIF-1α stimulated LASP1 expression in PDAC cells in vitro and mouse tumor xenografts in vivo. Clinically, LASP1 overexpression in PDAC patient specimens was associated significantly with lymph node metastasis and overall survival. Overall, our results defined LASP1 as a direct target gene for HIF-1α upregulation that is critical for metastatic progression of PDAC.

Identifying modifiers of glioma risk in patients with type I neurofibromatosis (NF1) could help support personalized tumor surveillance, advance understanding of gliomagenesis, and potentially identify novel therapeutic targets. Here, we report genetic polymorphisms in the human adenylate cyclase gene adenylate cyclase 8 (ADCY8) that correlate with glioma risk in NF1 in a sex-specific manner, elevating risk in females while reducing risk in males. This finding extends earlier evidence of a role for cAMP in gliomagenesis based on results in a genetically engineered mouse model (Nf1 GEM). Thus, sexually dimorphic cAMP signaling might render males and females differentially sensitive to variation in cAMP levels. Using male and female Nf1 GEM, we found significant sex differences exist in cAMP regulation and in the growth-promoting effects of cAMP suppression. Overall, our results establish a sex-specific role for cAMP regulation in human gliomagenesis, specifically identifying ADCY8 as a modifier of glioma risk in NF1. Cancer Res; 75(1); 1–6. ©2014 AACR.