Mitochondria-Associated Endoplasmic Reticulum Membranes in Breast Cancer

Mitochondria-associated ER membranes (MAMs) represent a crucial intracellular signaling hub, that regulates various cellular events including Ca2+ homeostasis, lipid metabolism, mitochondrial function, and cellular survival and death. All of these MAM-mediated cellular events contribute to carcinogenesis. Indeed, altered functions of MAMs in several types of cancers have been documented, in particular for breast cancer. Over the past years, altered expression of many MAM-resident proteins have been reported in breast cancer. These MAM-resident proteins play an important role in regulation of breast cancer initiation and progression. In the current review, we discuss our current knowledge about the functions of MAMs, and address the underlying mechanisms through which MAM-resident proteins regulate breast cancer. A fuller understanding of the pathways through which MAMs regulate breast cancer, and identification of breast cancer-specific MAM-resident proteins may help to develop novel therapeutic strategies for breast cancer.

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Tumor-Associated Macrophages: Critical Players in Drug Resistance of Breast Cancer

Frontiers in Immunology ◽

10.3389/fimmu.2021.799428 ◽

2021 ◽

Vol 12 ◽

Author(s):

Maoyu Xiao ◽

Jun He ◽

Liyang Yin ◽

Xiguan Chen ◽

Xuyu Zu ◽

...

Keyword(s):

Breast Cancer ◽

Drug Resistance ◽

Therapeutic Strategies ◽

Tumor Associated Macrophages ◽

Immune Microenvironment ◽

Tumor Immune Microenvironment ◽

Potential Possibility ◽

Underlying Mechanisms ◽

Novel Therapeutic Strategies

Drug resistance is one of the most critical challenges in breast cancer (BC) treatment. The occurrence and development of drug resistance are closely related to the tumor immune microenvironment (TIME). Tumor-associated macrophages (TAMs), the most important immune cells in TIME, are essential for drug resistance in BC treatment. In this article, we summarize the effects of TAMs on the resistance of various drugs in endocrine therapy, chemotherapy, targeted therapy, and immunotherapy, and their underlying mechanisms. Based on the current overview of the key role of TAMs in drug resistance, we discuss the potential possibility for targeting TAMs to reduce drug resistance in BC treatment, By inhibiting the recruitment of TAMs, depleting the number of TAMs, regulating the polarization of TAMs and enhancing the phagocytosis of TAMs. Evidences in our review support it is important to develop novel therapeutic strategies to target TAMs in BC to overcome the treatment of resistance.

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Altered Expression of TRIM Proteins-Inimical Outcome and Inimitable Oncogenic Function in Breast Cancer with Diverse Carcinogenic Hallmarks

Current Molecular Medicine ◽

10.2174/1566524022666220111122450 ◽

2022 ◽

Vol 22 ◽

Author(s):

Suman Kumar Ray ◽

Sukhes Mukherjee

Keyword(s):

Breast Cancer ◽

Intracellular Signaling ◽

Cancer Metastasis ◽

Protein Quality ◽

Breast Cancer Metastasis ◽

Cancer Prognosis ◽

Altered Expression ◽

Mesenchymal Transition ◽

Apoptosis Protein ◽

Trim Proteins

Abstract: Deregulation of ubiquitin-mediated degradation of oncogene products or tumor suppressors appears to be implicated in the genesis of carcinomas, according to new clinical findings. Conferring to recent research, some members of the tripartite motif (TRIM) proteins (a subfamily of the RING type E3 ubiquitin ligases) act as significant carcinogenesis regulators. Intracellular signaling, development, apoptosis, protein quality control, innate immunity, autophagy, and carcinogenesis are all regulated by TRIM family proteins, the majority of which have E3 ubiquitin ligase activity. The expression of TRIMs in tumors is likely to be related to the formation and/or progression of the disease, and TRIM expression could be used to predict cancer prognosis. Breast cancer is the most common malignancy in women and also the leading cause of death. TRIM family proteins have unique, vital activities, and their dysregulation, such as TRIM 21, promotes breast cancer, according to growing evidence. Many TRIM proteins have been identified as important cancer biomarkers, with decreased or elevated levels of expression. TRIM29 functions as a hypoxia-induced tumor suppressor gene, revealing a new molecular mechanism for ATM-dependent breast cancer suppression. In breast cancer cells, the TRIM28-TWIST1-EMT axis exists, and TRIM28 enhances breast cancer metastasis by stabilizing TWIST1 and thereby increasing epithelial-to-mesenchymal transition. Interestingly, many TRIM proteins are involved in the control of p53, and many TRIM proteins are likewise regulated by p53, according to current research. Furthermore, TRIMs linked to specific tumors may aid in the creation of innovative TRIM-targeted cancer treatments. This review focuses on TRIM proteins that are involved in tumor development, progression, and clinical significance in breast cancer.

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JAK2-mediated intracellular signaling

Current Molecular Medicine ◽

10.2174/1566524020666201015144702 ◽

2020 ◽

Vol 20 ◽

Author(s):

Mentor Sopjani ◽

Rifat Morina ◽

Valdet Uka ◽

Nguyen Thi Xuan ◽

Miribane Dërmaku-Sopjani

Keyword(s):

Receptor Tyrosine Kinase ◽

Intracellular Signaling ◽

Current Knowledge ◽

Janus Kinase ◽

Mediating Effects ◽

Signaling Mechanisms ◽

Recent Advances ◽

Underlying Mechanisms ◽

In The Beginning ◽

Molecular Regulatory Mechanisms

: Janus kinase-2 (JAK2) is a non-receptor tyrosine kinase that serves key roles as the intracellular signaling effector of the cytokine receptor, such as mediating effects of leptin, erythropoietin, interferon, and growth hormone. A lot of molecular underlying mechanisms of JAK2 participation are known, however, additional signaling mechanisms of its activation, regulation, and pleiotropic signaling roles are still being explored. Here, we review the current knowledge of JAK2- mediated cellular signaling at the molecular level. In the beginning, we will focus on the recent advances in JAK2 activation and regulation. A part of our review focuses on the JAK2 involvement in various diseases/conditions. Recent advances highlight the molecular regulatory mechanisms utilized by the JAK2 signaling, thus, enabling to consider alternative therapeutic strategies to treat various diseases/conditions mediated by JAK2 by using it as a therapeutic target.

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Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells—Deciphering Novel Potential Targets for a Cell Sensitization

Cancers ◽

10.3390/cancers10120495 ◽

2018 ◽

Vol 10 (12) ◽

pp. 495 ◽

Cited By ~ 11

Author(s):

Bastian Jakubzig ◽

Fabian Baltes ◽

Svenja Henze ◽

Martin Schlesinger ◽

Gerd Bendas

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Signaling Pathways ◽

Cell Lines ◽

Intracellular Signaling ◽

Breast Cancer Cells ◽

Mapk Pathway ◽

Resistance Mutations ◽

Underlying Mechanisms ◽

Mcf 7

Tumor cell binding to microenvironment components such as collagen type 1 (COL1) attenuates the sensitivity to cytotoxic drugs like cisplatin (CDDP) or mitoxantrone (MX), referred to as cell adhesion mediated drug resistance (CAM-DR). CAM-DR is considered as the onset for resistance mutations, but underlying mechanisms remain elusive. To evaluate CAM-DR as target for sensitization strategies, we analyzed signaling pathways in human estrogen-positive MCF-7 and triple-negative MDA-MB-231 breast cancer cells by western blot, proteome profiler array and TOP-flash assay in presence of COL1. β1-Integrins, known to bind COL1, appear as key for mediating COL1-related resistance in both cell lines that primarily follows FAK/PI3K/AKT pathway in MCF-7, and MAPK pathway in MDA-MB-231 cells. Notably, pCREB is highly elevated in both cell lines. Consequently, blocking these pathways sensitizes the cells evidently to CDDP and MX treatment. Wnt signaling is not relevant in this context. A β1-integrin knockdown of MCF-7 cells (MCF-7-β1-kd) reveals a signaling shift from FAK/PI3K/AKT to MAPK pathway, thus CREB emerges as a promising primary target for sensitization in MDA-MB-231, and secondary target in MCF-7 cells. Concluding, we provide evidence for importance of CAM-DR in breast cancer cells and identify intracellular signaling pathways as targets to sensitize cells for cytotoxicity treatment regimes.

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The Importance of Autophagy Regulation in Breast Cancer Development and Treatment

BioMed Research International ◽

10.1155/2014/710345 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 41

Author(s):

Joanna Magdalena Zarzynska

Keyword(s):

Breast Cancer ◽

Cell Growth ◽

Malignant Tumor ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Cell Stress ◽

Cancer Development ◽

Cancer Initiation ◽

Life Threatening

Breast cancer (BC) is a potentially life-threatening malignant tumor that still causes high mortality among women. One of the mechanisms through which cancer development could be controlled is autophagy. This process exerts different effects during the stages of cancer initiation and progression due to the occurring superimposition of signaling pathways of autophagy and carcinogenesis. Chronic inhibition of autophagy or autophagy deficiency promotes cancer, due to instability of the genome and defective cell growth and as a result of cell stress. However, increased induction of autophagy can become a mechanism which allows tumor cells to survive the conditions of hypoxia, acidosis, or chemotherapy. Therefore, in the development of cancer, autophagy is regarded as a double-edged sword. Determination of the molecular mechanisms underlying autophagy regulation and its role in tumorigenesis is an essential component of modern anticancer strategies. Results of scientific studies show that inhibition of autophagy may enhance the effectiveness of currently used anticancer drugs and other therapies (like radiotherapy). However, in some cases, the promotion of autophagy can induce death and, hence, elimination of the cancer cells and reduction of tumor size. This review summarizes the current knowledge on autophagy regulation in BC and up-to-date anticancer strategies correlated with autophagy.

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Current Strategies to Target Tumor-Associated-Macrophages to Improve Anti-Tumor Immune Responses

Cells ◽

10.3390/cells9010046 ◽

2019 ◽

Vol 9 (1) ◽

pp. 46 ◽

Cited By ~ 24

Author(s):

Anfray ◽

Ummarino ◽

Andón ◽

Allavena

Keyword(s):

Immune Responses ◽

Cancer Progression ◽

Tumor Tissue ◽

Tumor Response ◽

Current Knowledge ◽

Tumor Associated Macrophages ◽

Cancer Proliferation ◽

The Past ◽

Active Research ◽

Novel Therapeutic Strategies

: Established evidence demonstrates that tumor-infiltrating myeloid cells promote rather than stop-cancer progression. Tumor-associated macrophages (TAMs) are abundantly present at tumor sites, and here they support cancer proliferation and distant spreading, as well as contribute to an immune-suppressive milieu. Their pro-tumor activities hamper the response of cancer patients to conventional therapies, such as chemotherapy or radiotherapy, and also to immunotherapies based on checkpoint inhibition. Active research frontlines of the last years have investigated novel therapeutic strategies aimed at depleting TAMs and/or at reprogramming their tumor-promoting effects, with the goal of re-establishing a favorable immunological anti-tumor response within the tumor tissue. In recent years, numerous clinical trials have included pharmacological strategies to target TAMs alone or in combination with other therapies. This review summarizes the past and current knowledge available on experimental tumor models and human clinical studies targeting TAMs for cancer treatment.

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Mechanisms Causing Aging, Current Knowledge and the Way Forward

Journal of Advances in Medicine and Medical Research ◽

10.9734/jammr/2021/v33i2131152 ◽

2021 ◽

pp. 233-250

Author(s):

Gabriel Pisani ◽

Byron Baron

Keyword(s):

Current Knowledge ◽

Complex Diseases ◽

Aging Treatment ◽

New Wave ◽

Biochemical Basis ◽

Biochemical Processes ◽

The Past ◽

Causative Factors ◽

Underlying Mechanisms ◽

Shed Light

The rapid advancement in research technologies and bioinformatics over the past few decades has enabled researchers to shed light on the underlying mechanisms behind aging. Whilst the progress in understanding the biochemical processes involved is impressive, a lot more still needs to be uncovered before any potential effective anti-aging treatment can be produced. Unravelling the various root causes of aging is still the most important obstacle to overcome. The data available highlights that the most likely drivers of aging are the proteosome, the ribosome and telomeres. This review focuses largely on these factors and how they contribute to initiating aging and their targeting in potential therapy against the multitude of age-associated disorders. The investigation thus far of these causative factors will be presented. Understanding these root causes and how they cause aging is fundamental to present a way forward, such that the biochemical basis of aging can be discovered, in order to usher in a new wave of therapeutics against complex diseases.

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Hormone-mediated maternal effects in birds: mechanisms matter but what do we know of them?

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2007.0007 ◽

2007 ◽

Vol 363 (1497) ◽

pp. 1647-1661 ◽

Cited By ~ 294

Author(s):

Ton. G.G Groothuis ◽

Hubert Schwabl

Keyword(s):

Maternal Effects ◽

Current Knowledge ◽

Mechanistic Studies ◽

Maternal Circulation ◽

Apparent Lack ◽

The Past ◽

Trade Offs ◽

Underlying Mechanisms ◽

Almost All ◽

Pleiotropic Actions

Over the past decade, birds have proven to be excellent models to study hormone-mediated maternal effects in an evolutionary framework. Almost all these studies focus on the function of maternal steroid hormones for offspring development, but lack of knowledge about the underlying mechanisms hampers further progress. We discuss several hypotheses concerning these mechanisms, point out their relevance for ecological and evolutionary interpretations, and review the relevant data. We first examine whether maternal hormones can accumulate in the egg independently of changes in hormone concentrations in the maternal circulation. This is important for Darwinian selection and female physiological trade-offs, and possible mechanisms for hormone accumulation in the egg, which may differ among hormones, are reviewed. Although independent regulation of plasma and yolk concentrations of hormones is conceivable, the data are as yet inconclusive for ovarian hormones. Next, we discuss embryonic utilization of maternal steroids, since enzyme and receptor systems in the embryo may have coevolved with maternal effect mechanisms in the mother. We consider dose–response relationships and action pathways of androgens and argue that these considerations may help to explain the apparent lack of interference of maternal steroids with sexual differentiation. Finally, we discuss mechanisms underlying the pleiotropic actions of maternal steroids, since linked effects may influence the coevolution of parent and offspring traits, owing to their role in the mediation of physiological trade-offs. Possible mechanisms here are interactions with other hormonal systems in the embryo. We urge endocrinologists to embark on suggested mechanistic studies and behavioural ecologists to adjust their interpretations to accommodate the current knowledge of mechanisms.

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Inhibition of the Wnt Signalling Pathway: An Avenue to Control Breast Cancer Aggressiveness

International Journal of Molecular Sciences ◽

10.3390/ijms21239069 ◽

2020 ◽

Vol 21 (23) ◽

pp. 9069

Author(s):

Lorenzo Castagnoli ◽

Elda Tagliabue ◽

Serenella M. Pupa

Keyword(s):

Breast Cancer ◽

Stem Cell ◽

Current Knowledge ◽

Wnt Signalling ◽

Signalling Pathway ◽

Stem Cell Population ◽

Altered Expression ◽

Mesenchymal Transition ◽

Wnt Signalling Pathway ◽

Cancer Aggressiveness

Breast cancer (BC) is the most common tumour in women. Although the introduction of novel therapeutic approaches in clinical practice has dramatically improved the clinical outcome of BC patients, this malignant disease remains the second leading cause of cancer-related death worldwide. The wingless/integrated (Wnt) signalling pathway represents a crucial molecular node relevantly implicated in the regulation of normal somatic stem cells as well as cancer stem cell (CSC) traits and the epithelial–mesenchymal transition cell program. Accordingly, Wnt signalling is heavily dysregulated in BC, and the altered expression of different Wnt genes is significantly associated with cancer-related aggressive behaviours. For all these reasons, Wnt signalling represents a promising therapeutic target currently under clinical investigation to achieve cancer eradication by eliminating CSCs, considered by most to be responsible for tumour initiation, relapse, and drug resistance. In this review, we summarized the current knowledge on the Wnt signalling pathway in BC and have presented evidence implicating the suitability of Wnt targeting in an attempt to improve the outcome of patients without affecting the normal somatic stem cell population.

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Intrinsic adriamycin resistance in p53-mutated breast cancer is related to the miR-30c/FANCF/REV1-mediated DNA damage response

Cell Death and Disease ◽

10.1038/s41419-019-1871-z ◽

2019 ◽

Vol 10 (9) ◽

Cited By ~ 4

Author(s):

Shu Lin ◽

Lifeng Yu ◽

Xinyue Song ◽

Jia Bi ◽

Longyang Jiang ◽

...

Keyword(s):

Breast Cancer ◽

Genetic Alterations ◽

Complementation Group ◽

P53 Mutation ◽

Mutant P53 ◽

Intrinsic Resistance ◽

Novel Mirna ◽

Mutational Status ◽

Underlying Mechanisms ◽

Novel Therapeutic Strategies

Abstract Adriamycin(ADR) is still considered to be one of the most effective agents in the treatment of breast cancer (BrCa), its efficacy is compromised by intrinsic resistance or acquire characteristics of multidrug resistance. At present, there are few genetic alterations that can be exploited as biomarkers to guide targeted use of ADR in clinical. Therefore, exploring the determinants of ADR sensitivity is pertinent for their optimal clinical application. TP53 is the most frequently mutated gene in human BrCa, p53 mutation has been reported to be closely related to ADR resistance, whereas the underlying mechanisms that cause endogenous ADR resistance in p53-mutant BrCa cells are not completely understood. The aim of the present study was to investigate the potential roles of miRNA in the response to ADR in p53-mutated breast cancer. Here, we report that BrCa cells expressing mutp53 are more resistant to ADR than cells with wild-type p53 (wtp53). The DNA repair protein- Fanconi anemia complementation group F protein (FANCF) and the translesion synthesis DNA polymerase REV1 protein is frequently abundant in the context of mutant p53 of BrCa. By targeting two key factors, miR-30c increases the sensitivity of BrCa cells to ADR. Furthermore, p53 directly activates the transcription of miR-30c by binding to its promoter. Subsequent analyses revealed that p53 regulates REV1 and FANCF by modulating miR-30c expression. Mutation of the p53 abolished this response. Consistently, reduced miR-30c expression is highly correlated with human BrCa with p53 mutational status and is associated with poor survival. We propose that one of the pathways affected by mutant p53 to increase intrinsic resistance to ADR involves miR-30c downregulation and the consequent upregulation of FANCF and REV1. The novel miRNA-mediated pathway that regulates chemoresistance in breast cancer will facilitate the development of novel therapeutic strategies.

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