The effect of an exopolysaccharide probiotic molecule from on breast cancer cells.

Introduction: Many well-known risk factors for breast cancer are associated with dysbiosis (an aberrant microbiome). However, how bacterial products modulate cancer are poorly understood. In this study, we investigated the effect of an exopolysaccharide (EPS) produced by the commensal bacterium on breast cancer phenotypes.

Targeting Breast Cancer Stem Cells Using Naturally Occurring Phytoestrogens.

Breast cancer therapies have made significant strides in improving survival for patients over the past decades. However, recurrence and drug resistance continue to challenge long-term recurrence-free and overall survival rates. Mounting evidence supports the cancer stem cell model in which the existence of a small population of breast cancer stem cells (BCSCs) within the tumor enables these cells to evade conventional therapies and repopulate the tumor, giving rise to more aggressive, recurrent tumors.

Notch Signaling in Breast Cancer: A Role in Drug Resistance.

Breast cancer is a heterogeneous disease that can be subdivided into unique molecular subtypes based on protein expression of the Estrogen Receptor, Progesterone Receptor, and/or the Human Epidermal Growth Factor Receptor 2. Therapeutic approaches are designed to inhibit these overexpressed receptors either by endocrine therapy, targeted therapies, or combinations with cytotoxic chemotherapy. However, a significant percentage of breast cancers are inherently resistant or acquire resistance to therapies, and mechanisms that promote resistance remain poorly understood.

DAXX-inducing phytoestrogens inhibit ER+ tumor initiating cells and delay tumor development.

Recurrence of estrogen receptor (ER)-positive breast tumors despite curative-intent adjuvant therapy is thought to be due to enrichment of tumor initiating cells (TIC) during endocrine therapy (ET). Recently, it was identified that by antagonizing the ER, ET promotes rapid degradation of the death-associated factor 6 (DAXX) protein, which is necessary and sufficient to potently inhibit TICs. Thus, the goal of the current study was to identify a DAXX-inducing agent to inhibit TICs and prevent proliferation of the tumor.

DAXX Suppresses Tumor-Initiating Cells in Estrogen Receptor-Positive Breast Cancer Following Endocrine Therapy.

Estrogen receptor (ER)-positive breast cancer recurrence is thought to be driven by tumor-initiating cells (TIC). TICs are enriched by endocrine therapy through NOTCH signaling. Side effects have limited clinical trial testing of NOTCH-targeted therapies.

Inhibition of HER2 Increases JAGGED1-dependent Breast Cancer Stem Cells: Role for Membrane JAGGED1.

HER2-positive breast cancer is driven by cells possessing stem-like properties of self-renewal and differentiation, referred to as cancer stem cells (CSC). CSCs are implicated in radiotherapy, chemotherapy resistance, and tumor recurrence. NOTCH promotes breast CSC survival and self-renewal, and overexpression of NOTCH1 and the NOTCH ligand JAGGED1 predict poor outcome.

Notch-1-PTEN-ERK1/2 signaling axis promotes HER2+ breast cancer cell proliferation and stem cell survival.

Trastuzumab targets the HER2 receptor on breast cancer cells to attenuate HER2-driven tumor growth. However, resistance to trastuzumab-based therapy remains a major clinical problem for women with HER2+ breast cancer. Breast cancer stem cells (BCSCs) are suggested to be responsible for drug resistance and tumor recurrence.

Preclinical study of a Kv11.1 potassium channel activator as antineoplastic approach for breast cancer.

Potassium ion (K) channels have been recently found to play a critical role in cancer biology. Despite that pharmacologic manipulation of ion channels is recognized as an important therapeutic approach, very little is known about the effects of targeting of K channels in cancer. In this study, we demonstrate that use of the Kv11.

Deubiquitinase OTUD6B Isoforms Are Important Regulators of Growth and Proliferation.

Unlabelled: Deubiquitinases (DUB) are increasingly linked to the regulation of fundamental processes in normal and cancer cells, including DNA replication and repair, programmed cell death, and oncogenes and tumor suppressor signaling. Here, evidence is presented that the deubiquitinase OTUD6B regulates protein synthesis in non-small cell lung cancer (NSCLC) cells, operating downstream from mTORC1. OTUD6B associates with the protein synthesis initiation complex and modifies components of the 48S preinitiation complex.

Cancer stem cells and HER2 positive breast cancer: The story so far.

Human Epidermal Growth Factor Receptor type 2 (HER2) gene amplification and/or protein overexpression is observed in patients suffering from HER2+ breast cancer. This subtype of breast cancer has improved prognosis due to availability of anti-HER2 therapy. However, drug resistance and tumor recurrence still remains a major concern.

ATG9A loss confers resistance to trastuzumab via c-Cbl mediated Her2 degradation.

Acquired or de novo resistance to trastuzumab remains a barrier to patient survival and mechanisms underlying this still remain unclear. Using stable isotope labelling by amino acids in cell culture (SILAC)-based quantitative proteomics to compare proteome profiles between trastuzumab sensitive/resistant cells, we identified autophagy related protein 9A (ATG9A) as a down-regulated protein in trastuzumab resistant cells (BT474-TR). Interestingly, ATG9A ectopic expression markedly decreased the proliferative ability of BT474-TR cells but not that of the parental line (BT474).

The role of Rak in the regulation of stability and function of BRCA1.

BRCA1 is an important player in the DNA damage response signaling, and its deficiency results in genomic instability. A complete loss or significantly reduced BRCA1 protein expression is often found in sporadic breast cancer cases despite the absence of genetic or epigenetic aberrations, suggesting the existence of other regulatory mechanisms controlling BRCA1 protein expression. Herein, we demonstrate that Fyn-related kinase (Frk)/Rak plays an important role in maintaining genomic stability, possibly in part through positively regulating BRCA1 protein stability and function via tyrosine phosphorylation on BRCA1 Tyr1552.

PKCα Attenuates Jagged-1-Mediated Notch Signaling in ErbB-2-Positive Breast Cancer to Reverse Trastuzumab Resistance.

Purpose: Breast cancer is the second leading cause of cancer mortality among women worldwide. The major problem with current treatments is tumor resistance, recurrence, and disease progression. ErbB-2-positive breast tumors are aggressive and frequently become resistant to trastuzumab or lapatinib.

Human Epidermal Growth Factor Receptor 2 (HER2) Impedes MLK3 Kinase Activity to Support Breast Cancer Cell Survival.

Human epidermal growth factor receptor 2 (HER2) is amplified in ∼ 15-20% of human breast cancer and is important for tumor etiology and therapeutic options of breast cancer. Up-regulation of HER2 oncogene initiates cascades of events cumulating to the stimulation of transforming PI3K/AKT signaling, which also plays a dominant role in supporting cell survival and efficacy of HER2-directed therapies. Although investigating the underlying mechanisms by which HER2 promotes cell survival, we noticed a profound reduction in the kinase activity of a pro-apoptotic mixed lineage kinase 3 (MLK3) in HER2-positive (HER2+) but not in HER2-negative (HER2-) breast cancer tissues, whereas both HER2+ and HER2- tumors expressed a comparable level of MLK3 protein.

Notch-EGFR/HER2 Bidirectional Crosstalk in Breast Cancer.

The Notch pathway is a well-established mediator of cell-cell communication that plays a critical role in stem cell survival, self-renewal, cell fate decisions, tumorigenesis, invasion, metastasis, and drug resistance in a variety of cancers. An interesting form of crosstalk exists between the Notch receptor and the Epidermal Growth Factor Receptor Tyrosine Kinase family, which consists of HER-1, -2, -3, and -4. Overexpression of HER and/or Notch occurs in several human cancers including brain, lung, breast, ovary, and skin making them potent oncogenes capable of advancing malignant disease.

Gamma secretase inhibitors of Notch signaling.

The numerous processes involved in the etiology of breast cancer such as cell survival, metabolism, proliferation, differentiation, and angiogenesis are currently being elucidated. However, underlying mechanisms that drive breast cancer progression and drug resistance are still poorly understood. As we discuss here in detail, the Notch signaling pathway is an important regulatory component of normal breast development, cell fate of normal breast stem cells, and proliferation and survival of breast cancer initiating cells.

The functional role of Notch signaling in triple-negative breast cancer.

The term "triple-negative breast cancer" (TNBC) is a heterogeneous subtype of breast cancer. Unfortunately, due to the lack of expression of hormone receptors and human epidermal growth factor receptor-2, therefore the lack of US Food and Drug Administration-approved targeted therapies, TNBC has the worst prognosis of all subtypes of breast cancer. Notch signaling has emerged as a pro-oncogene in several human malignancies and has particularly been associated with the triple-negative subtype of breast cancer.

Evaluation of biomarkers in multifocal/multicentric invasive breast carcinomas.

Background: The purpose of this study was to evaluate whether breast carcinoma biomarkers vary among separate tumor foci of multifocal/multicentric (MF/MC) breast carcinomas and whether this variation correlates with morphological features and tumor grade.

Design: We reviewed the biomarker profiles of MF/MC invasive breast carcinomas diagnosed between January 2001 and June 2010 at our institution. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal receptor protein (HER2) results were classified as positive or negative.

The Effect of Cold Ischemia Time and/or Formalin Fixation on Estrogen Receptor, Progesterone Receptor, and Human Epidermal Growth Factor Receptor-2 Results in Breast Carcinoma.

Aims. To compare the results of estrogen and progesterone receptors (ER, PR), and human epidermal growth factor receptor-2 (HER2) expression status on biopsy and excision specimens and to evaluate the effect of cold ischemia time and/or formalin fixation on these biomarkers. Methods.

NOTCH-1 and NOTCH-4 are novel gene targets of PEA3 in breast cancer: novel therapeutic implications.

Introduction: Women with triple-negative breast cancer have the worst prognosis, frequently present with metastatic tumors and have few targeted therapy options. Notch-1 and Notch-4 are potent breast oncogenes that are overexpressed in triple-negative and other subtypes of breast cancer. PEA3, an ETS transcription factor, is also overexpressed in triple-negative and other breast cancer subtypes.

Targeting Notch to target cancer stem cells.

The cellular heterogeneity of neoplasms has been at the center of considerable interest since the "cancer stem cell hypothesis", originally formulated for hematologic malignancies, was extended to solid tumors. The origins of cancer "stem" cells (CSC) or tumor-initiating cells (TIC; henceforth referred to as CSCs) and the methods to identify them are hotly debated topics. Nevertheless, the existence of subpopulations of tumor cells with stem-like characteristics has significant therapeutic implications.

Trastuzumab resistance: role for Notch signaling.

Epidermal growth factor receptor-2 (ErbB-2/HER2) is a potent breast oncogene that has been shown to be amplified in 20% of breast cancers. Overexpression of ErbB-2 predicts for aggressive tumor behavior, resistance to some cytotoxic and antihormonal therapies, and poor overall survival. Trastuzumab, the humanized, monoclonal antibody directed against ErbB-2 has shown tremendous efficacy and improved overall survival for women when combined with a taxane-based chemotherapy.

Notch versus the proteasome: what is the target of gamma-secretase inhibitor-I?

gamma-Secretase inhibitors are new anti-cancer agents targeting Notch signaling. Their specificity for Notch is as yet unclear. Han and colleagues investigated the effects of Z-LeuLeuNleu-CHO on growth of breast cancer cells.