Context-Dependent Estrogenic Actions of (+)-Pisatin Produced in Elicited Green or Snow Pea ().

Legumes are a predominant source of isoflavones, termed phytoestrogens, that mimic 17β-estradiol (E2). Phytoalexins are inducible isoflavones produced in plants subjected to environmental stressors (e.g.

The Anticancer Effects of the Garlic Organosulfide Diallyl Trisulfide through the Attenuation of B[a]P-Induced Oxidative Stress, AhR Expression, and DNA Damage in Human Premalignant Breast Epithelial (MCF-10AT1) Cells.

Benzo[a]pyrene (B[a]P) is the most characterized polycyclic aromatic hydrocarbon associated with breast cancer. Our lab previously reported that the organosulfur compound (OSC), diallyl trisulfide (DATS), chemoprevention mechanism works through the induction of cell cycle arrest and a reduction in oxidative stress and DNA damage in normal breast epithelial cells. We hypothesize that DATS will inhibit B[a]P-induced cancer initiation in premalignant breast epithelial (MCF-10AT1) cells.

Novel Therapeutic Combination Targets the Growth of Letrozole-Resistant Breast Cancer through Decreased Cyclin B1.

As breast cancer cells transition from letrozole-sensitive to letrozole-resistant, they over-express epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK), and human epidermal growth factor receptor 2 (HER2) while acquiring enhanced motility and epithelial-to-mesenchymal transition (EMT)-like characteristics that are attenuated and reversed by glyceollin treatment, respectively. Interestingly, glyceollin inhibits the proliferation and tumor progression of triple-negative breast cancer (TNBC) and estrogen-independent breast cancer cells; however, it is unlikely that a single phytochemical would effectively target aromatase-inhibitor (AI)-resistant metastatic breast cancer in the clinical setting. Since our previous report indicated that the combination of lapatinib and glyceollin induced apoptosis in hormone-dependent AI-resistant breast cancer cells, we hypothesized that combination therapy would also be beneficial for hormone independent letrozole-resistant breast cancer cells (LTLT-Ca) compared to AI-sensitive breast cancer cells (AC-1) by decreasing the expression of proteins associated with proliferation and cell cycle progression.

A Novel Allosteric Inhibitor Targets PLK1 in Triple Negative Breast Cancer Cells.

While Polo-like kinase 1 (PLK1) inhibitors have shown promise in clinical settings for treating triple-negative breast cancer tumors and other solid tumors, they are limited by their ability to bind non-selectively to the ATP kinase domain. Therefore, we sought to develop a PLK1 allosteric inhibitor targeting the PLK1 T-loop (a switch responsible for activation) and evaluate its effects in triple-negative breast cancer cells. A novel compound, RK-10, was developed based on an in silico model, and its effects on specificity, viability, migration, and cell cycle regulation in MCF-10A and MDA-MB 231 cells were evaluated.

Glyceollins Trigger Anti-Proliferative Effects in Hormone-Dependent Aromatase-Inhibitor-Resistant Breast Cancer Cells through the Induction of Apoptosis.

Aromatase inhibitors (AIs) are standard treatment for estrogen-dependent postmenopausal breast tumors; however, resistance develops leading to tumor relapse and metastasis. We previously demonstrated that glyceollin inhibits proliferation, survival, and migration of hormone-independent letrozole-resistant breast cancer. Since many AI-resistant tumors remain hormone-dependent, identifying distinctions between estrogen-receptor-positive (ER+) and ER-negative (ER-) AI-resistant tumor response to therapy is critical.

Diallyl Sulfide Attenuation of Carcinogenesis in Mammary Epithelial Cells through the Inhibition of ROS Formation, and DNA Strand Breaks.

Garlic has long been used medicinally for many diseases, including cancer. One of the active garlic components is diallyl sulfide (DAS), which prevents carcinogenesis and reduces the incidence rate of several cancers. In this study, non-cancerous MCF-10A cells were used as a model to investigate the effect of DAS on Benzo (a)pyrene (BaP)-induced cellular carcinogenesis.

Mammospheres of letrozole-resistant breast cancer cells enhance breast cancer aggressiveness.

Aromatase inhibitors (AIs), such as letrozole, are considered as first-line treatment for estrogen receptor-positive breast cancer in postmenopausal women. Despite the successful use of letrozole, resistance to therapy, tumor relapse and metastasis remain principal causes of patient mortality. Although there is no therapy currently available for AI-resistant breast cancer, previous reports have demonstrated that AI resistance is associated with hormone independence, increased growth factor signaling, enhanced cellular motility and epithelial to mesenchymal transition (EMT).

Quantitative Proteomic Profiling Identifies a Potential Novel Chaperone Marker in Resistant Breast Cancer.

Development of aromatase inhibitor resistant breast cancer among postmenopausal women continues to be a major clinical obstacle. Previously, our group demonstrated that as breast cancer cells transition from hormone-dependent to hormone-independent, they are associated with increased growth factor signaling, enhanced cellular motility, and the epithelial to mesenchymal transition (EMT). Given the complexity of cancer stem cells (CSC) and their implications on endocrine resistance and EMT, we sought to understand their contribution towards the development of aromatase inhibitor resistant breast cancer.

Acquisition of Letrozole Resistance Through Activation of the p38/MAPK Signaling Cascade.

Background/aim: Previous reports identified a global proteomic signature of estrogen-independent letrozole resistant breast cancer cells, however, it remains unclear how letrozole-resistance is impacted when cells remain estrogen receptor positive (ER+).

Materials And Methods: To capture the protein expression profile associated with ER+ Aromatase inhibitor (AI) resistance, a global proteomic analysis was conducted using the letrozole-sensitive (T47Darom cells) and letrozole-resistant cells (T47DaromLR cells). To examine the molecular features associated with this phenotype Kaplan- Meier analysis, phospho-antibody arrays, proliferation and apoptosis assays were conducted.

A novel and cost-effective orthotopic model for the study of human breast cancer in mouse mammary gland organ culture.

Mouse mammary organ culture (MMOC) is used to evaluate the efficacy of chemopreventive agents against the development of carcinogen-induced preneoplastic lesions and is highly correlative to carcinogenesis models. Here, we developed a new MMOC model, by introducing human breast cancer cells into the mouse mammary gland. This novel model, termed human breast cancer in MMOC (BCa-MMOC), mimics orthotopic breast cancer mouse models.

Phytochemicals: Current strategies for treating breast cancer.

Females with early-stage metastatic, estrogen-dependent breast cancer are generally treated with surgery, radiation and chemotherapy, or with more targeted approaches such as aromatase inhibitors (anastrozole or letrozole) or anti-estrogens (tamoxifen). Despite widespread successful usage of these agents for the treatment of breast cancer, resistance, tumor relapse and metastasis remain the principal causes of mortality for patients with breast cancer. While numerous groups have made major contributions toward an improved understanding of resistance mechanisms, the currently insufficient grasp of the most critical pathways involved in resistance is evident in the inability to adequately treat and drastically improve patient outcomes in females with hormone-refractory breast cancer, including triple negative breast cancer.

Protein Kinase CK2 Expression Predicts Relapse Survival in ERα Dependent Breast Cancer, and Modulates ERα Expression in Vitro.

The heterotetrameric protein kinase CK2 has been associated with oncogenic transformation, and our previous studies have shown that it may affect estrogenic signaling. Here, we investigate the role of the protein kinase CK2 in regulating ERα (estrogen receptor α) signaling in breast cancer. We determined the correlation of CK2α expression with relapse free breast cancer patient survival utilizing Kaplan Meier Plotter (kmplot.

Glyceollin I Reverses Epithelial to Mesenchymal Transition in Letrozole Resistant Breast Cancer through ZEB1.

Although aromatase inhibitors are standard endocrine therapy for postmenopausal women with early-stage metastatic estrogen-dependent breast cancer, they are limited by the development of drug resistance. A better understanding of this process is critical towards designing novel strategies for disease management. Previously, we demonstrated a global proteomic signature of letrozole-resistance associated with hormone-independence, enhanced cell motility and implications of epithelial mesenchymal transition (EMT).

Benzimidazoles diminish ERE transcriptional activity and cell growth in breast cancer cells.

Estrogen receptors (ERα and ERβ) are members of the nuclear receptor superfamily. They regulate the transcription of estrogen-responsive genes and mediate numerous estrogen related diseases (i.e.

Proteomic signatures of acquired letrozole resistance in breast cancer: suppressed estrogen signaling and increased cell motility and invasiveness.

Aromatase inhibitors, such as letrozole, have become the first-line treatment for postmenopausal women with estrogen-dependent breast cancer. However, acquired resistance remains a major clinical obstacle. Previous studies demonstrated constitutive activation of the MAPK signaling, overexpression of HER2, and down-regulation of aromatase and ERα in letrozole-resistant breast cancer cells.

In vitro and in vivo evaluation of novel anticancer agents in triple negative breast cancer models.

Triple negative breast cancer (TNBC) is subtype of breast disease devoid of the estrogen, progesterone, and Her2/neu receptors which are targets for pharmacological intervention. There is a need for novel anti-breast cancer agents that target TNBC. Therefore, novel isochalcone DJ52 was evaluated using the alamar blue dye exclusion assay, the luciferase colony assay, and xenograft models to determine its efficacy and potency.

Phytoalexins, miRNAs and breast cancer: a review of phytochemical-mediated miRNA regulation in breast cancer.

There is growing interest in the diverse signaling pathways that regulate and affect breast tumorigenesis, including the role of phytochemicals and the emerging role of microRNAs (miRNAs). Recent studies demonstrate that miRNAs regulate fundamental cellular and developmental processes at the transcriptional and translational level under normal and disease conditions. While there is growing evidence to support the role of phytoalexin-mediated miRNA regulation of cancer, few reports address this role in breast cancer.

Insulin-like growth factor-1 signaling regulates miRNA expression in MCF-7 breast cancer cell line.

In breast carcinomas, increased levels of insulin-like growth factor 1 (IGF-1) can act as a mitogen to augment tumorigenesis through the regulation of MAPK and AKT signaling pathways. Signaling through these two pathways allows IGF-1 to employ mechanisms that favor proliferation and cellular survival. Here we demonstrate a subset of previously described tumor suppressor and oncogenic microRNAs (miRNAs) that are under the direct regulation of IGF-1 signaling.

Glyceollins as novel targeted therapeutic for the treatment of triple-negative breast cancer.

The purpose of this study was to investigate the effects of glyceollins on the suppression of tumorigenesis in triple-negative breast carcinoma cell lines. We further explored the effects of glyceollins on microRNA and protein expression in MDA-MB-231 cells. Triple-negative (ER-, PgR- and Her2/neu-) breast carcinoma cells were used to test the effects of glyceollins on tumorigenesis in vivo.

Endocrine disruptor regulation of microRNA expression in breast carcinoma cells.

Background: Several environmental agents termed "endocrine disrupting compounds" or EDCs have been reported to bind and activate the estrogen receptor-α (ER). The EDCs DDT and BPA are ubiquitously present in the environment, and DDT and BPA levels in human blood and adipose tissue are detectable in most if not all women and men. ER-mediated biological responses can be regulated at numerous levels, including expression of coding RNAs (mRNAs) and more recently non-coding RNAs (ncRNAs).

Environmental signaling and reproduction: a comparative biological and chemical perspective.

Reproduction is a critical element of life. Self-propagation in all living organisms ranging from bacteria to humans involves numerous common strategies. Underlying all reproductive strategies is the essential need for signaling molecules to initiate and maintain the process.

Effects of SDF-1-CXCR4 signaling on microRNA expression and tumorigenesis in estrogen receptor-alpha (ER-α)-positive breast cancer cells.

The majority of breast cancer cases ultimately become unresponsive to endocrine therapies, and this progression of breast cancer from hormone-responsive to hormone-independent represents an area in need of further research. Additionally, hormone-independent carcinomas are characterized as being more aggressive and metastatic, key features of more advanced disease. Having previously shown the ability of the stromal-cell derived factor-1 (SDF-1)-CXCR4 signaling axis to promote primary tumorigenesis and hormone independence by overexpressing CXCR4 in MCF-7 cells, in this study we further examined the role of SDF-1/CXCR4 in the endogenously CXCR4-positive, estrogen receptor α (ER-α)-positive breast carcinoma cell line, MDA-MB-361.

Upregulation of AIB1, aromatase and ERα provides long-term estrogen-deprived human breast cancer cells with a mechanistic growth advantage for survival.

To investigate the mechanisms by which breast cancer cells adapt and are able to grow during estrogen deprivation, human estrogen receptor-α (ERα)-positive breast cancer cells stably transfected with the aromatase gene (MCF-7Ca) were cultured in steroid-depleted medium for 6-8 months until they started proliferating. Compared with the parental MCF-7Ca cells, long-term estrogen-deprived UMB-1Ca cells exhibited increased aromatase activity (2000%), AIB1 expression (3500%) and ERα expression (100%). When MCF-7Ca cells were isolated from tumors of mice treated for 12 months with an aromatase inhibitor, letrozole, ERα was reduced (50%) whereas AIB1 levels were increased (>1000%), suggesting that the mechanism of estrogen deprivation might predetermine the signaling pathway utilized.

Cytokine receptor CXCR4 mediates estrogen-independent tumorigenesis, metastasis, and resistance to endocrine therapy in human breast cancer.

Estrogen independence and progression to a metastatic phenotype are hallmarks of therapeutic resistance and mortality in breast cancer patients. Metastasis has been associated with chemokine signaling through the SDF-1-CXCR4 axis. Thus, the development of estrogen independence and endocrine therapy resistance in breast cancer patients may be driven by SDF-1-CXCR4 signaling.

Upregulation of AIB1, aromatase and ERα provides long-term estrogen-deprived human breast cancer cells with a mechanistic growth advantage for survival.

To investigate the mechanisms by which breast cancer cells adapt and are able to grow during estrogen deprivation, human estrogen receptor-α (ERα)-positive breast cancer cells stably transfected with the aromatase gene (MCF-7Ca) were cultured in steroid-depleted medium for 6-8 months until they started proliferating. Compared with the parental MCF-7Ca cells, long-term estrogen-deprived UMB-1Ca cells exhibited increased aromatase activity (2000%), AIB1 expression (3500%) and ERα expression (100%). When MCF-7Ca cells were isolated from tumors of mice treated for 12 months with an aromatase inhibitor, letrozole, ERα was reduced (50%) whereas AIB1 levels were increased (>1000%), suggesting that the mechanism of estrogen deprivation might predetermine the signaling pathway utilized.