Cellular reprogramming by the conjoint action of ERα, FOXA1, and GATA3 to a ligand‐inducible growth state

Kong, Say Li; Li, Guoliang; Loh, Siang Lin; Sung, Wing-Kin; Liu, Edison T.

doi:10.1038/msb.2011.59

Cited by 173 publications

(154 citation statements)

References 38 publications

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“…Recent whole genome analysis identified a GATA3 mutation which exists in 14% of luminal A breast cancer [35]. It was reported that ERα, FOXA1 and GATA3 form a functional enhanceosome to drive the transcription of ERα-regulated genes in breast cancer cells [36,37]. High FOXA1 and GATA3 expression might therefore affect endocrine responsiveness and prognosis in ER-positive breast cancer [38].…”

Section: Discussionmentioning

confidence: 99%

Differential expression of progesterone receptor, FOXA1, GATA3, and p53 between pre- and postmenopausal women with estrogen receptor-positive breast cancer

Hosoda

Yamamoto

Nakano

et al. 2014

Breast Cancer Res Treat

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Estrogen receptor (ER) is essential for estrogen-dependent growth, and its level of expression is considered a crucial determinant of response to endocrine therapy and prognosis in ER-positive breast cancer. On the other hand, the clinical role of progesterone receptor (PgR) in ER-positive breast cancer remains controversial, although testing of PgR by immunohistochemistry (IHC) has become routine. Recent studies indicated that plasma estradiol levels were related to expression levels of estrogen-responsive genes in ER-positive breast cancer tissues in both preand postmenopausal women. In this study, we analyzed expression levels of estrogen-responsive genes (PgR and TFF1), a progesterone-responsive gene (RANKL), ER-related genes (FOXA1 and GATA3), HER2, Ki67 and p53 in ER-positive, HER2-negative breast cancer tissues by IHC.Correlations between expression levels of these molecular markers and clinicopathological factors, including prognosis, were compared between pre-and postmenopausal women. Serum levels of estrone, estradiol, progesterone and testosterone were also measured. Expression levels of PgR, TFF1, RANKL and GATA3 were significantly higher in premenopausal women than in postmenopausal women. Serum estradiol levels were positively correlated with Ki67 labeling index (LI) in premenopausal women, but not in postmenopausal women. High expression of FOXA1 and GATA3 was significantly associated with improved disease-free survival in premenopausal women, but not in postmenopausal women, whereas high expression of PgR and low expression of p53 was significantly correlated with improved disease-free survival in postmenopausal women, but not in premenopausal women. Moreover, the best cutoff points of 3 Ki67 LI for disease-free survival were 30% for premenopausal women and 14% for postmenopausal women. Expression levels of ER, TFF1 and RANKL were not associated with disease-free survival in either pre-or postmenopausal women. Our results suggest that the mechanisms of development and estrogen-dependent growth of ER-positive breast cancer might differ according to menopausal status.

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Section: Discussionmentioning

confidence: 99%

Differential expression of progesterone receptor, FOXA1, GATA3, and p53 between pre- and postmenopausal women with estrogen receptor-positive breast cancer

Hosoda

Yamamoto

Nakano

et al. 2014

Breast Cancer Res Treat

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“…Indeed, GATA3 levels increase upon EZH2 silencing, mediating a decrease in bi-lineage cell numbers (Granit et al 2012). Interestingly, the three genes with the greatest negative correlation with VGLL1 and miR-934 in the TCGA dataset were GATA3, ESR1, and FOXA1, which form a functional enhanceosome that regulates the genes driving core ERa functions and that co-operatively modulates the transcriptional networks previously ascribed to ERa alone (Kong et al 2011). Gain and loss of function in vitro studies are currently in progress in our group, using miR-934/VGLL1-negative (MCF7 and T47d) and VGLL1-positive (SKBR3 and MDA-MB-468) cell lines, respectively, that will confirm the suggested role of miR-934 in the modulation of ESR1 expression and the maintenance of a luminal progenitor phenotype.…”

Section: Discussionmentioning

confidence: 99%

VGLL1 expression is associated with a triple-negative basal-like phenotype in breast cancer

Castilla¹,

López-García²,

Atienza³

et al. 2014

Endocrine-Related Cancer

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Vestigial-like 1 (VGLL1) is a poorly characterized gene encoding a transcriptional co-activator structurally homologous to TAZ and YAP that modulates the Hippo pathway in Drosophila. In this study, we examined the expression of VGLL1 and its intronic miRNA, miR-934, in breast cancer. VGLL1 and miR-934 expression miRNA profiling was carried out on frozen samples of grade 3 invasive ductal carcinomas. VGLL1 protein was also examined in 433 sporadic and BRCA1-associated breast carcinomas on tissue microarrays. RNA-seq data from The Cancer Genome Atlas (TCGA) was used to confirm differences in VGLL1 and miR-934 expression in different breast cancer subtypes, and to correlate their expression with that of other genes and miRNAs. Of 28 miRNAs differentially expressed in estrogen receptor (ER)-positive and ER-negative grade 3 breast carcinomas, miR-934 was most strongly upregulated in ER-negative carcinomas, and its expression was correlated with that of VGLL1. Nuclear VGLL1 expression was observed in 13% of sporadic breast carcinomas, and while VGLL1 was only occasionally found in luminal A (0.70%) and B (5.60%) carcinomas, it was often expressed in HER2-positive (17%), triple-negative (TN) breast carcinomas (O40%) and BRCA1-associated TN carcinomas (O50%). These findings were confirmed in the TCGA dataset, which revealed positive associations with luminal progenitor genes (GABRP, SLC6A14, FOXC1, PROM1, and BBOX1) and strong negative correlations with ER-associated genes (ESR1, C6ORF211, GATA3, and FOXA1). Moreover, VGLL1 expression was associated with reduced overall survival. In conclusion, VGLL1 and miR-934 are mainly expressed in sporadic and BRCA1-associated TN basal-like breast carcinomas, and their coordinated expression, at least partially mediated by the direct modulation of ESR1, might be involved in the maintenance of a luminal progenitor phenotype.

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“…4a). GATA3 is an important transcriptional regulator in both normal mammary gland development and breast cancer [39][40][41] , and low expression levels of GATA3 are associated with a poor prognosis 42 . Three genes, PTCH1, PPARA and NFIB, exhibit epistatic interactions with GATA3 and also display negatively correlated expression levels with GATA3 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Widespread genetic epistasis among cancer genes

Wang

McNerney

et al. 2014

Nat Commun

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Quantitative genetic epistasis has been hypothesized to be an important factor in the development and progression of complex diseases. Cancers in particular are driven by the accumulation of mutations that may act epistatically during the course of the disease. However, as cancer mutations are uncovered at an unprecedented rate, determining which combinations of genetic alterations interact to produce cancer phenotypes remains a challenge. Here we show that by using combinatorial RNAi screening in cell culture, dense and often previously undetermined interactions among cancer genes were revealed by assessing gene pairs that are frequently co-altered in primary breast cancers. These interacting gene pairs are significantly associated with survival time when co-altered in patients, indicating that genetic interaction mapping may be leveraged to improve risk assessment. As many of these interacting gene pairs involve known drug targets, personalized treatment regimens may be improved by overlaying genetic interactions with mutational profiling.

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Cellular reprogramming by the conjoint action of ERα, FOXA1, and GATA3 to a ligand‐inducible growth state

Cited by 173 publications

References 38 publications

Differential expression of progesterone receptor, FOXA1, GATA3, and p53 between pre- and postmenopausal women with estrogen receptor-positive breast cancer

Differential expression of progesterone receptor, FOXA1, GATA3, and p53 between pre- and postmenopausal women with estrogen receptor-positive breast cancer

VGLL1 expression is associated with a triple-negative basal-like phenotype in breast cancer

Widespread genetic epistasis among cancer genes

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