scholarly journals Associations between Pregnane X Receptor and Breast Cancer Growth and Progression

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2295
Author(s):  
Bradley A. Creamer ◽  
Shelly N. B. Sloan ◽  
Jennifer F. Dennis ◽  
Robert Rogers ◽  
Sidney Spencer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Nuclear Receptor ◽  
Breast Tissue ◽  
Current Knowledge ◽  
Acquired Resistance ◽  
Pregnane X Receptor ◽  
Chemotherapeutic Agents ◽  
Bile Acid Metabolism ◽  
Cytochrome P450 Enzymes ◽  
Cellular Detoxification

Pregnane X receptor (PXR, NR1I2) is a member of the ligand-activated nuclear receptor superfamily. This receptor is promiscuous in its activation profile and is responsive to a broad array of both endobiotic and xenobiotic ligands. PXR is involved in pivotal cellular detoxification processes to include the regulation of genes that encode key drug-metabolizing cytochrome-P450 enzymes, oxidative stress response, as well as enzymes that drive steroid and bile acid metabolism. While PXR clearly has important regulatory roles in the liver and gastrointestinal tract, this nuclear receptor also has biological functions in breast tissue. In this review, we highlight current knowledge of PXR’s role in mammary tumor carcinogenesis. The elevated level of PXR expression in cancerous breast tissue suggests a likely interface between aberrant cell division and xeno-protection in cancer cells. Moreover, PXR itself exerts positive effect on the cell cycle, thereby predisposing tumor cells to unchecked proliferation. Activation of PXR also plays a key role in regulating apoptosis, as well as in acquired resistance to chemotherapeutic agents. The repressive role of PXR in regulating inflammatory mediators along with the existence of genetic polymorphisms within the sequence of the PXR gene may predispose individuals to developing breast cancer. Further investigations into the role that PXR plays in driving tumorigenesis are needed.

scholarly journals Mechanisms of Resistance to CDK4/6 Inhibitors in Breast Cancer and Potential Biomarkers of Response

Breast Care ◽  
2017 ◽  
Vol 12 (5) ◽  
pp. 304-308 ◽  
Author(s):  
Cristina Guarducci ◽  
Martina Bonechi ◽  
Giulia Boccalini ◽  
Matteo Benelli ◽  
Emanuela Risi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Molecular Mechanisms ◽  
Randomized Clinical Trials ◽  
De Novo ◽  
Current Knowledge ◽  
Acquired Resistance ◽  
Metastatic Breast ◽  
Molecular Alterations ◽  
Potential Biomarkers

Randomized clinical trials demonstrated that CDK4/6 inhibitors are highly effective in patients with hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer in combination with endocrine therapy. The use of CDK4/6 inhibitors in clinics is becoming common for patients with HR+/HER2- metastatic breast cancer and will certainly increase in the near future. However, patients might show de novo or acquired resistance to these drugs. Molecular alterations have been suggested as determinants for de novo resistance to CDK4/6 inhibitors, but have never been validated in a clinical setting. In addition, molecular mechanisms of acquired resistance to palbociclib have been analyzed only in preclinical studies. Here we review the current knowledge on the available preclinical data about the mechanisms of de novo and acquired resistance to CDK4/6 inhibitors in breast cancer, and clinical data about potential biomarkers of response.

scholarly journals Regulation of CAR and PXR Expression in Health and Disease

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2395
Author(s):  
Martine Daujat-Chavanieu ◽  
Sabine Gerbal-Chaloin
Keyword(s):  
Transcription Factors ◽  
Nuclear Receptor ◽  
Current Knowledge ◽  
Constitutive Androstane Receptor ◽  
Adult Life ◽  
Pregnane X Receptor ◽  
Regulatory Mechanisms ◽  
Nuclear Receptor Superfamily ◽  
Pathological Conditions ◽  
Health And Disease

Pregnane X receptor (PXR, NR1I2) and constitutive androstane receptor (CAR, NR1I3) are members of the nuclear receptor superfamily that mainly act as ligand-activated transcription factors. Their functions have long been associated with the regulation of drug metabolism and disposition, and it is now well established that they are implicated in physiological and pathological conditions. Considerable efforts have been made to understand the regulation of their activity by their cognate ligand; however, additional regulatory mechanisms, among which the regulation of their expression, modulate their pleiotropic effects. This review summarizes the current knowledge on CAR and PXR expression during development and adult life; tissue distribution; spatial, temporal, and metabolic regulations; as well as in pathological situations, including chronic diseases and cancers. The expression of CAR and PXR is modulated by complex regulatory mechanisms that involve the interplay of transcription factors and also post-transcriptional and epigenetic modifications. Moreover, many environmental stimuli affect CAR and PXR expression through mechanisms that have not been elucidated.

scholarly journals The Connection of Azole Fungicides with Xeno-Sensing Nuclear Receptors, Drug Metabolism and Hepatotoxicity

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1192 ◽  
Author(s):  
Philip Marx-Stoelting ◽  
Constanze Knebel ◽  
Albert Braeuning
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Liver Tumors ◽  
Current Knowledge ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Receptor Activation ◽  
Azole Fungicides

Azole fungicides, especially triazole compounds, are widely used in agriculture and as pharmaceuticals. For a considerable number of agricultural azole fungicides, the liver has been identified as the main target organ of toxicity. A number of previous studies points towards an important role of nuclear receptors such as the constitutive androstane receptor (CAR), the pregnane-X-receptor (PXR), or the aryl hydrocarbon receptor (AHR), within the molecular pathways leading to hepatotoxicity of these compounds. Nuclear receptor-mediated hepatic effects may comprise rather adaptive changes such as the induction of drug-metabolizing enzymes, to hepatocellular hypertrophy, histopathologically detectable fatty acid changes, proliferation of hepatocytes, and the promotion of liver tumors. Here, we present a comprehensive review of the current knowledge of the interaction of major agricultural azole-class fungicides with the three nuclear receptors CAR, PXR, and AHR in vivo and in vitro. Nuclear receptor activation profiles of the azoles are presented and related to histopathological findings from classic toxicity studies. Important issues such as species differences and multi-receptor agonism and the consequences for data interpretation and risk assessment are discussed.

scholarly journals FBI-1 enhanced the resistance of triple-negative breast cancer cells to chemotherapeutic agents via the miR-30c/PXR axis

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Hua Yang ◽  
Lili Ren ◽  
Yanan Wang ◽  
Xuebing Bi ◽  
Xiaoli Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Antitumor Agents ◽  
Pregnane X Receptor ◽  
Chemotherapeutic Agents ◽  
Multiple Roles ◽  
Tnbc Cell

Abstract The factor that binds to the inducer of short transcripts‐1 (FBI-1) is a transcription suppressor and an important proto‐oncogene that plays multiple roles in carcinogenesis and therapeutic resistance. In the present work, our results indicated that FBI-1 enhanced the resistance of triple-negative breast cancer (TNBC) cells to chemotherapeutic agents by repressing the expression of micoRNA-30c targeting the pregnane X receptor (PXR). The expression of FBI-1 was positively related to PXR and its downstream drug resistance-related genes in TNBC tissues. FBI-1 enhanced the expression of PXR and enhanced the activation of the PXR pathway. The miR-30c decreased the expression of PXR by targeting the 3′-UTR of PXR, and FBI-1 increased the expression of PXR by repressing miR-30c’s expression. Through the miR-30c/PXR axis, FBI-1 accelerated the clearance or elimination of antitumor agents in TNBC cells (the TNBC cell lines or the patients derived cells [PDCs]) and induced the resistance of cells to antitumor agents. Therefore, the results indicated that the miR-30c/PXR axis participates in the FBI-1-mediated drug-resistance of TNBC cells.

scholarly journals Chemotherapy-triggered changes in stromal compartment drive tumor invasiveness and progression of breast cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Jana Plava ◽  
Monika Burikova ◽  
Marina Cihova ◽  
Lenka Trnkova ◽  
Bozena Smolkova ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Breast Tissue ◽  
Chorioallantoic Membrane ◽  
Chemotherapeutic Agents ◽  
Surrounding Tissue ◽  
Molecular Characteristics ◽  
Stromal Compartment ◽  
Angiogenic Potential

Abstract Background Chemotherapy remains a standard treatment option for breast cancer despite its toxic effects to normal tissues. However, the long-lasting effects of chemotherapy on non-malignant cells may influence tumor cell behavior and response to treatment. Here, we have analyzed the effects of doxorubicin (DOX) and paclitaxel (PAC), commonly used chemotherapeutic agents, on the survival and cellular functions of mesenchymal stromal cells (MSC), which comprise an important part of breast tumor microenvironment. Methods Chemotherapy-exposed MSC (DOX-MSC, PAC-MSC) were co-cultured with three breast cancer cell (BCC) lines differing in molecular characteristics to study chemotherapy-triggered changes in stromal compartment of the breast tissue and its relevance to tumor progression in vitro and in vivo. Conditioned media from co-cultured cells were used to determine the cytokine content. Mixture of BCC and exposed or unexposed MSC were subcutaneously injected into the immunodeficient SCID/Beige mice to analyze invasion into the surrounding tissue and possible metastases. The same mixtures of cells were applied on the chorioallantoic membrane to study angiogenic potential. Results Therapy-educated MSC differed in cytokine production compared to un-exposed MSC and influenced proliferation and secretory phenotype of tumor cells in co-culture. Histochemical tumor xenograft analysis revealed increased invasive potential of tumor cells co-injected with DOX-MSC or PAC-MSC and also the presence of nerve fiber infiltration in tumors. Chemotherapy-exposed MSC have also influenced angiogenic potential in the model of chorioallantoic membrane. Conclusions Data presented in this study suggest that neoadjuvant chemotherapy could possibly alter otherwise healthy stroma in breast tissue into a hostile tumor-promoting and metastasis favoring niche. Understanding of the tumor microenvironment and its complex net of signals brings us closer to the ability to recognize the mechanisms that prevent failure of standard therapy and accomplish the curative purpose.

scholarly journals Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 846 ◽  
Author(s):  
Samson Samuel ◽  
Elizabeth Varghese ◽  
Peter Kubatka ◽  
Chris Triggle ◽  
Dietrich Büsselberg
Keyword(s):  
Breast Cancer ◽  
Clinical Studies ◽  
Current Knowledge ◽  
Chemotherapeutic Agents ◽  
Cancer Drug ◽  
Rapid Progression ◽  
Future Prospects ◽  
Anti Cancer ◽  
Cancer Agent ◽  
Tumor Agent

Interest has grown in studying the possible use of well-known anti-diabetic drugs as anti-cancer agents individually or in combination with, frequently used, chemotherapeutic agents and/or radiation, owing to the fact that diabetes heightens the risk, incidence, and rapid progression of cancers, including breast cancer, in an individual. In this regard, metformin (1, 1-dimethylbiguanide), well known as ‘Glucophage’ among diabetics, was reported to be cancer preventive while also being a potent anti-proliferative and anti-cancer agent. While meta-analysis studies reported a lower risk and incidence of breast cancer among diabetic individuals on a metformin treatment regimen, several in vitro, pre-clinical, and clinical studies reported the efficacy of using metformin individually as an anti-cancer/anti-tumor agent or in combination with chemotherapeutic drugs or radiation in the treatment of different forms of breast cancer. However, unanswered questions remain with regards to areas such as cancer treatment specific therapeutic dosing of metformin, specificity to cancer cells at high concentrations, resistance to metformin therapy, efficacy of combinatory therapeutic approaches, post-therapeutic relapse of the disease, and efficacy in cancer prevention in non-diabetic individuals. In the current article, we discuss the biology of metformin and its molecular mechanism of action, the existing cellular, pre-clinical, and clinical studies that have tested the anti-tumor potential of metformin as a potential anti-cancer/anti-tumor agent in breast cancer therapy, and outline the future prospects and directions for a better understanding and re-purposing of metformin as an anti-cancer drug in the treatment of breast cancer.

Targeting Different Pathways Using Novel Combination Therapy in Triple Negative Breast Cancer

2020 ◽  
Vol 20 (8) ◽  
pp. 586-602
Author(s):  
Manzoor A. Mir ◽  
Hina Qayoom ◽  
Umar Mehraj ◽  
Safura Nisar ◽  
Basharat Bhat ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Combination Therapy ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Single Agent ◽  
Acquired Resistance ◽  
Pi3k Pathway ◽  
Chemotherapeutic Agents ◽  
High Grade ◽  
Efficient Treatment

Triple negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer accounting for 15-20% of cases and is defined by the lack of hormonal receptors viz., estrogen receptor (ER), progesterone receptor (PR) and expression of human epidermal growth receptor 2 (HER2). Treatment of TNBC is more challenging than other subtypes of breast cancer due to the lack of markers for the molecularly targeted therapies (ER, PR, and HER-2/ Neu), the conventional chemotherapeutic agents are still the mainstay of the therapeutic protocols of its patients. Despite, TNBC being more chemo-responsive than other subtypes, unfortunately, the initial good response to the chemotherapy eventually turns into a refractory drug-resistance. Using a monotherapy for the treatment of cancer, especially high-grade tumors like TNBC, is mostly worthless due to the inherent genetic instability of tumor cells to develop intrinsic and acquired resistance. Thus, a cocktail of two or more drugs with different mechanisms of action is more effective and could successfully control the disease. Furthermore, combination therapy reveals more, or at least the same, effectiveness with lower doses of every single agent and decreases the likelihood of chemoresistance. Herein, we shed light on the novel combinatorial approaches targeting PARP, EGFR, PI3K pathway, AR, and wnt signaling, HDAC, MEK pathway for efficient treatment of high-grade tumors like TNBC and decreasing the onset of resistance.

scholarly journals Halophilic Carotenoids and Breast Cancer: From Salt Marshes to Biomedicine

Marine Drugs ◽  
2021 ◽  
Vol 19 (11) ◽  
pp. 594
Author(s):  
Micaela Giani ◽  
Yoel Genaro Montoyo-Pujol ◽  
Gloria Peiró ◽  
Rosa María Martínez-Espinosa
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Anticancer Agents ◽  
Hormone Receptors ◽  
Current Knowledge ◽  
Antioxidant Properties ◽  
Growth Factor Receptor ◽  
Chemotherapeutic Agents ◽  
In Vivo Studies ◽  
Great Promise

Breast cancer is the leading cause of death among women worldwide. Over the years, oxidative stress has been linked to the onset and progression of cancer. In addition to the classical histological classification, breast carcinomas are classified into phenotypes according to hormone receptors (estrogen receptor—RE—/progesterone receptor—PR) and growth factor receptor (human epidermal growth factor receptor—HER2) expression. Luminal tumors (ER/PR-positive/HER2-negative) are present in older patients with a better outcome. However, patients with HER2-positive or triple-negative breast cancer (TNBC) (ER/PR/HER2-negative) subtypes still represent highly aggressive behavior, metastasis, poor prognosis, and drug resistance. Therefore, new alternative therapies have become an urgent clinical need. In recent years, anticancer agents based on natural products have been receiving huge interest. In particular, carotenoids are natural compounds present in fruits and vegetables, but algae, bacteria, and archaea also produce them. The antioxidant properties of carotenoids have been studied during the last years due to their potential in preventing and treating multiple diseases, including cancer. Although the effect of carotenoids on breast cancer during in vitro and in vivo studies is promising, clinical trials are still inconclusive. The haloarchaeal carotenoid bacterioruberin holds great promise to the future of biomedicine due to its particular structure, and antioxidant activity. However, much work remains to be performed to draw firm conclusions. This review summarizes the current knowledge on pre-clinical and clinical analysis on the use of carotenoids as chemopreventive and chemotherapeutic agents in breast cancer, highlighting the most recent results regarding the use of bacterioruberin from haloarchaea.

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