Navigating the Blood-Brain Barrier: Challenges and Therapeutic Strategies in Breast Cancer Brain Metastases.

Breast cancer (BC) is the most common cancer in women, with metastatic BC being responsible for the highest number of deaths. A frequent site for BC metastasis is the brain. Brain metastasis derived from BC involves the cooperation of multiple genetic, epigenetic, angiogenic, and tumor-stroma interactions.

Comparison of Fixation Methods for the Detection of Claudin 1 and E-Cadherin in Breast Cancer Cell Lines by Immunofluorescence.

The tight junction membrane protein claudin 1 and the adherens junction protein E-cadherin play critical roles in cell-cell communication and in cell signaling. As a result, their protein levels and distribution in cancer have been a focus of cancer researchers in recent years. The loss of sensitivity to contact inhibition and the establishment of invasive properties in cancer are thought to be a result of the mislocalization of these membrane proteins to the cytoplasm.

The Breast Tumor Microenvironment: A Key Player in Metastatic Spread.

The tumor microenvironment plays a pivotal role in the tumorigenesis, progression, and metastatic spread of many cancers including breast. There is now increasing evidence to support the observations that a bidirectional interplay between breast cancer cells and stromal cells exists within the tumor and the tumor microenvironment both at the primary tumor site and at the metastatic site. This interaction occurs through direct cell to cell contact, or by the release of autocrine or paracrine factors which can activate pro-tumor signaling pathways and modulate tumor behavior.

Generation of prolactin-inducible protein (Pip) knockout mice by CRISPR/Cas9-mediated gene engineering.

Prolactin-inducible protein (PIP) is a multifunctional glycoprotein that is highly expressed and found in the secretions of apocrine glands such as salivary, lacrimal, and sweat glands including the mammary glands. PIP has been implicated in various diseases, including breast cancer, gross cystic disease of the breast, keratoconus of the eye, and the autoimmune Sjögren's syndrome. Here we have generated a knockout (KO) mouse using the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRSPR-associated (Cas)9 system.

Claudin 1 Is Highly Upregulated by PKC in MCF7 Human Breast Cancer Cells and Correlates Positively with PKCε in Patient Biopsies.

Recent studies provide compelling evidence to suggest that the tight junction protein claudin 1, aberrantly expressed in several cancer types, plays an important role in cancer progression. Dysregulation of claudin 1 has been shown to induce epithelial mesenchymal transition (EMT). Furthermore, activation of the ERK signaling pathway by protein kinase C (PKC) was shown to be necessary for EMT induction.

Identification of Claudin 1 Transcript Variants in Human Invasive Breast Cancer.

Background: The claudin 1 tight junction protein, solely responsible for the barrier function of epithelial cells, is frequently down regulated in invasive human breast cancer. The underlying mechanism is largely unknown, and no obvious mutations in the claudin 1 gene (CLDN1) have been identified to date in breast cancer. Since many genes have been shown to undergo deregulation through splicing and mis-splicing events in cancer, the current study was undertaken to investigate the occurrence of transcript variants for CLDN1 in human invasive breast cancer.

Idiopathic Hypogonadotropic Hypogonadism Caused by Inactivating Mutations in SRA1.

Objective: What initiates the pubertal process in humans and other mammals is still unknown. We hypothesized that gene(s) taking roles in triggering human puberty may be identified by studying a cohort of idiopathic hypogonadotropic hypogonadism (IHH).

Methods: A cohort of IHH cases was studied based on autozygosity mapping coupled with whole exome sequencing.

Dynamic Histone Acetylation of H3K4me3 Nucleosome Regulates MCL1 Pre-mRNA Splicing.

Pre-mRNA splicing is a cotranscriptional process affected by the chromatin architecture along the body of coding genes. Recruited to the pre-mRNA by splicing factors, histone deacetylases (HDACs) and K-acetyltransferases (KATs) catalyze dynamic histone acetylation along the gene. In colon carcinoma HCT 116 cells, HDAC inhibition specifically increased KAT2B occupancy as well as H3 and H4 acetylation of the H3K4 trimethylated (H3K4me3) nucleosome positioned over alternative exon 2 of the MCL1 gene, an event paralleled with the exclusion of exon 2.

Claudin 1 in Breast Cancer: New Insights.

Claudin 1 is a small transmembrane protein responsible for maintaining the barrier function that exists between epithelial cells. A tight junction protein that regulates the paracellular transport of small ions across adjacent cells, claudin 1 maintains cellular polarity and plays a major role in cell-cell communication and epithelial cell homeostasis. Long considered to be a putative tumor suppressor in human breast cancer, new studies suggest a role much more complex.

The steroid receptor RNA activator protein (SRAP) controls cancer cell migration/motility.

The steroid receptor RNA activator gene (SRA1) produces both a functional RNA (SRA) and a protein (SRAP), whose exact physiological roles remain unknown. To identify cellular processes regulated by SRAP we compared the transcriptome of Hela and MDA-MB-231 cancer cells upon depletion of the SRA/SRAP transcripts or overexpression of the SRAP protein. RNA-seq and Ontology analyses pinpointed cellular movement as potentially regulated by SRAP.

PDK2-mediated alternative splicing switches Bnip3 from cell death to cell survival.

Herein we describe a novel survival pathway that operationally links alternative pre-mRNA splicing of the hypoxia-inducible death protein Bcl-2 19-kD interacting protein 3 (Bnip3) to the unique glycolytic phenotype in cancer cells. While a full-length Bnip3 protein (Bnip3FL) encoded by exons 1-6 was expressed as an isoform in normal cells and promoted cell death, a truncated spliced variant of Bnip3 mRNA deleted for exon 3 (Bnip3Δex3) was preferentially expressed in several human adenocarcinomas and promoted survival. Reciprocal inhibition of the Bnip3Δex3/Bnip3FL isoform ratio by inhibiting pyruvate dehydrogenase kinase isoform 2 (PDK2) in Panc-1 cells rapidly induced mitochondrial perturbations and cell death.

Claudin 1 promotes migration and increases sensitivity to tamoxifen and anticancer drugs in luminal-like human breast cancer cells MCF7.

Downregulation of claudin 1, a critical tight junction protein, has been correlated with increased invasiveness in breast cancer. However, recent studies suggest that claudin 1 contributes to the progression of some molecular subtypes of breast cancer. In this study, claudin 1 promotes migration in luminal-like MCF7 human breast cancer cells and increases their sensitivity to tamoxifen, etoposide, and cisplatin.

Claudin 1 Promotes Migration and Increases Sensitivity to Tamoxifen and Anticancer Drugs in Luminal-like Human Breast Cancer Cells MCF7.

Downregulation of claudin 1, a critical tight junction protein, has been correlated with increased invasiveness in breast cancer. However, recent studies suggest that claudin 1 contributes to the progression of some molecular subtypes of breast cancer. In this study, claudin 1 promotes migration in luminal-like MCF7 human breast cancer cells and increases their sensitivity to tamoxifen, etoposide, and cisplatin.

Towards further defining the proteome of mouse saliva.

Background: Knowledge of the mouse salivary proteome is not well documented and as a result, very limited. Currently, several salivary proteins remain unidentified and for some others, their function yet to be determined. The goal of the present study is to utilize mass spectrometry analysis to widen our knowledge of mouse salivary proteins, and through extensive database searches, provide further insight into the array of proteins that can be found in saliva.

RNA-dependent dynamic histone acetylation regulates MCL1 alternative splicing.

Histone deacetylases (HDACs) and lysine acetyltransferases (KATs) catalyze dynamic histone acetylation at regulatory and coding regions of transcribed genes. Highly phosphorylated HDAC2 is recruited within corepressor complexes to regulatory regions, while the nonphosphorylated form is associated with the gene body. In this study, we characterized the nonphosphorylated HDAC2 complexes recruited to the transcribed gene body and explored the function of HDAC-complex-mediated dynamic histone acetylation.

Steroid receptor RNA activator protein (SRAP) expression as a prognostic factor in ER+ human breast tumors.

Background: The steroid receptor RNA activator protein (SRAP) is a newly described protein modulating the activity of multiple transcription factors including the estrogen receptor (ER). We have recently reported the immunodetection by Western blot of multiple SRAP peptides in breast tissue. High expression of these peptides, assessed by tissue micro-array (TMA) analysis, was associated with poor prognosis in patients whose primary tumors were ER positive (ER+).

Claudin 1 expression in basal-like breast cancer is related to patient age.

Background: Defects in tight junctions, gate-keepers of the integrity of the epidermal barrier function, are known to contribute to cancer development. As such, enhancing our understanding of how the expression of proteins involved in these junctions is regulated in cancer, remains a priority. Although the expression of one of these proteins, claudin 1, is down regulated in most invasive human breast cancers (HBC), we have recently shown that high levels of claudin 1, characterized tumors belonging to the very aggressive basal-like breast cancer (BLBC) subtype.

Expression of both estrogen receptor-beta 1 (ER-β1) and its co-regulator steroid receptor RNA activator protein (SRAP) are predictive for benefit from tamoxifen therapy in patients with estrogen receptor-alpha (ER-α)-negative early breast cancer (EBC).

Background: Roles of Estrogen Receptor-beta 1 (ER-β1) and its co-regulator Steroid Receptor RNA Activator Protein (SRAP) in breast cancer remain unclear. Previously, ER-β1 and SRAP expression were found positively correlated in breast cancer and, therefore, expression of these two molecules could characterize cancers with a distinct clinical outcome.

Patients And Methods: ER-β1 and SRAP expression was determined by immunohistochemistry (IHC) in tissue microarrays from a randomized, placebo-controlled trial (NCIC-CTG-MA12), designed to determine the benefit of tamoxifen following chemotherapy in premenopausal early breast cancer (EBC).

A bi-faceted role of estrogen receptor β in breast cancer.

Despite over 15 years of research, the exact role, if any, played by estrogen receptor β (ERβ) in human breast cancer remains elusive. A large body of data both in vitro and in vivo supports its role as an antiproliferative, pro-apoptotic factor especially when co-expressed with ERα. However, there is a smaller body of data associating ERβ with growth and survival in breast cancer.

The role of estrogen receptor-β in breast cancer.

The discovery of a second estrogen receptor (ER), ERβ, has led to a reevaluation of estrogen action. The widespread expression of ERβ-like proteins in normal and neoplastic mammary tissues suggests a role of ERβ in the breast. Little progress has been made in elucidating this role or roles, but the presence of two ERs and variant isoforms in breast cancers presents challenges and opportunities to tease out complexities in understanding the estrogen signaling pathway in breast tissues.

Steroid Receptor RNA Activator bi-faceted genetic system: Heads or Tails?

The Steroid Receptor RNA Activator (SRA) was first identified by Lanz et al. in 1999 as a functional non-coding RNA able to co-activate steroid nuclear receptors. Since this incipient study, our understanding of SRA as a broader co-regulator of nuclear receptors as well as other transcription factors has greatly expanded.

Comparative evaluation of ERα and ERβ significance in breast cancer: state of the art.

Over 30 years of clinical data have unequivocally established estrogen receptor (ER)-α as a critical clinical biomarker and valid therapeutic target to fight breast cancer. However, ERα remains imperfect with respect to both of these activities, mainly because the mechanisms by which estrogens mediate their activity are far more complex than originally anticipated. The cloning of a second estrogen receptor, ERβ, has led to a full re-evaluation of our original view of the action of estrogen in breast tissues.

A novel hypoxia-inducible spliced variant of mitochondrial death gene Bnip3 promotes survival of ventricular myocytes.

Rationale: Alternative splicing provides a versatile mechanism by which cells generate proteins with different or even antagonistic properties. Previously, we established hypoxia-inducible death factor Bnip3 as a critical component of the intrinsic death pathway.

Objective: To investigate alternative splicing of Bnip3 pre-mRNA in postnatal ventricular myocytes during hypoxia.

Claudin 1 in breast tumorigenesis: revelation of a possible novel "claudin high" subset of breast cancers.

Claudins are the major component of the tight junctions in epithelial cells and as such play a key role in the polarized location of ion channels, receptors, and enzymes to the different membrane domains. In that regard, claudins are necessary for the harmonious development of a functional epithelium. Moreover, defective tight junctions have been associated with the development of neoplastic phenotype in epithelial cells.