Triple-negative breast cancer (TNBC) represents a unique subgroup of breast cancers (BCa) with potential to be highly proliferative and invasive. Patient with TNBC are prone to developing resistance to chemotherapy. Therefore, TNBC usually has a poor clinical outcome. The key factors driving these malignant features remain poorly understood. In this study, we report for the first time that expression levels of FOXE3, a recently identified lens-specific transcription factor, were preferentially upregulated in TNBC tissues compared to non-TNBC tissues, and this upregulation correlated well to a poor overall/recurrence-free survival in patients. Depletion of FOXE3 in TNBC cell lines promoted cell death, cell cycle arrest, and potentiated sensitivity to docetaxel (DTX), a first-line chemotherapeutic drug for TNBC treatment. These alterations in cell growth/survival properties were accompanied by induction of CDKN1B, a gene encoding the tumor suppressor p27. We further provided the molecular evidence that FOXE3 could directly bind to the CDKN1B promoter and negatively regulate its transcription in TNBC cells. Importantly, knockdown of combined p27 and FOXE3 reversed the DTX-induced cell growth inhibition observed upon FOXE3 knockdown, indicating that the FOXE3\'s effects on TNBC progression were mediated mainly through transcriptional regulation of the p27 signaling. Together, our findings suggest that FOXE3 may function as a potent oncogene during the progression of TNBC, likely affecting cell proliferation, invasion and chemosensitivity, and functioning at least in part through transcriptional repression of p27 signaling.

Objective To investigate the influence of Msx2 conditional gene knockout during lens development in mice. Methods Lens-specific Msx2 knockout mice were generated using the Cre-loxP system. The eyes of Msx2 conditional knockout ( Msx2CKO) and wild-type ( Msx2WT) mice were examined during embryonic and early postnatal periods using histological, immunofluorescence, in situ hybridization, cell proliferation, apoptosis, and mRNA microarray analyses. Results Msx2CKO mice exhibited small lens formation and microphthalmia after birth, while Msx2CKO embryos exhibited a persistent lens stalk, small lens formation, and microphthalmia. Conditional deletion of Msx2 also led to an increased apoptosis rate, a significant reduction in FoxE3 expression, and an upregulation of Prox1 expression in the lens vesicle during the early embryonic period. Microarray comparison of Msx2CKO and Msx2WT lens transcriptomes identified a large number of differentially expressed genes. Real-time PCR showed that Casp8 and Casp3 expression was upregulated in Msx2CKO mice at post-natal day 1. Conclusion The activation of apoptosis through the caspase-8/caspase-3 signaling pathway, together with the downregulation of FoxE3 expression, appeared to account for the smaller lens formation in Msx2CKO mice.

Microphthalmia and anophthalmia (MA) are severe developmental eye anomalies, many of which are likely to have an underlying genetic cause. More than 30 genes have been described, each of which is responsible for a small percentage of these anomalies. Among these, is the FOXE3 gene, which was initially described in individuals with dominantly inherited anterior segment dysgenesis and, subsequently, associated with recessively inherited primary aphakia, sclerocornea and microphthalmia. In this work, we describe 8 individuals presenting with an MA phenotype. Among them, 7 are carrying biallelic recessive FOXE3 mutations and 2 of these have novel mutations: p.(Ala78Thr) and p.(Arg104Cys). The last of our patients is carrying in the heterozygous state the recessive p.(Arg90Leu) mutation in the FOXE3 gene. To further understand FOXE3 involvement in this wide spectrum of ocular anomalies with 2 different patterns of inheritance, we reviewed all individuals with ocular abnormalities described in the literature for which a FOXE3 mutation was identified. This review demonstrates that correlations exist between the mutation type, mode of inheritance and the phenotype severity. Furthermore, understanding the genetic basis of these conditions will contribute to overall understanding of eye development, improve the quality of care, genetic counseling and, in future, gene-based therapies.

To report the findings in a patient with congenital primary aphakia, a rare disease known to be caused by mutations in the FOXE3 gene.
The clinical appearances and visual functions of the patient were determined from the medical records. Genetic analyses were performed to search for mutations in the FOXE3 gene by Sanger sequencing and whole exome sequencing.
The 2-month-old male patient first presented with bilateral congenital aphakia associated with microphthalmia, corneal opacity, and dysplasia of the anterior segment. At the age of 2-years, his visual acuity in the left eye was 20/1000 at 30 cm, he was able to discriminate red, blue, and yellow light stimuli, and a b-wave was recorded by scotopic combined rod-cone electroretinograms. The right eye became blind during the follow-up period. No mutation in the FOXE3 gene was detected.
Although congenital aphakia is known to be caused by mutations in the FOXE3 gene, the results of lack of coding mutation in this patient suggests a possible genetic heterogeneity of the disease.

Clinical evaluation and mutation analysis was performed in 51 consecutive probands with severe eye malformations - anophthalmia and/or severe microphthalmia - seen in a single specialist ophthalmology center. The mutation analysis consisted of bidirectional sequencing of the coding regions of SOX2, OTX2, PAX6 (paired domain), STRA6, BMP4, SMOC1, FOXE3, and RAX, and genome-wide array-based copy number assessment. Fifteen (29.4%) of the 51 probands had likely causative mutations affecting SOX2 (9/51), OTX2 (5/51), and STRA6 (1/51). Of the cases with bilateral anophthalmia, 9/12 (75%) were found to be mutation positive. Three of these mutations were large genomic deletions encompassing SOX2 (one case) or OTX2 (two cases). Familial inheritance of three intragenic, plausibly pathogenic, and heterozygous mutations was observed. An unaffected carrier parent of an affected child with an identified OTX2 mutation confirmed the previously reported nonpenetrance for this disorder. Two families with SOX2 mutations demonstrated a parent and child both with significant but highly variable eye malformations. Heterozygous loss-of-function mutations in SOX2 and OTX2 are the most common genetic pathology associated with severe eye malformations and bi-allelic loss-of-function in STRA6 is confirmed as an emerging cause of nonsyndromal eye malformations.

Anophthalmia and microphthalmia (AM) are the most severe malformations of the eye, corresponding respectively to reduced size or absent ocular globe. Wide genetic heterogeneity has been reported and different genes have been demonstrated to be causative of syndromic and non-syndromic forms of AM. We screened seven AM genes [GDF6 (growth differentiation factor 6), FOXE3 (forkhead box E3), OTX2 (orthodenticle protein homolog 2), PAX6 (paired box 6), RAX (retina and anterior neural fold homeobox), SOX2 (SRY sex determining region Y-box 2), and VSX2 (visual system homeobox 2 gene)] in a cohort of 150 patients with isolated or syndromic AM. The causative genetic defect was identified in 21% of the patients (32/150). Point mutations were identified by direct sequencing of these genes in 25 patients (13 in SOX2, 4 in RAX, 3 in OTX2, 2 in FOXE3, 1 in VSX2, 1 in PAX6, and 1 in GDF6). In addition eight gene deletions (five SOX2, two OTX2 and one RAX) were identified using a semi-quantitative multiplex polymerase chain reaction (PCR) [quantitative multiplex PCR amplification of short fluorescent fragments (QMPSF)]. The causative genetic defect was identified in 21% of the patients. This result contributes to our knowledge of the molecular basis of AM, and will facilitate accurate genetic counselling.