Abstract Breast cancer is the most common form of cancer diagnosed in women worldwide and the second leading cause of cancer-related deaths in the USA. Despite the development of newer diagnostic ...methods, selective as well as targeted chemotherapies and their combinations, surgery, hormonal therapy, radiotherapy, breast cancer recurrence, metastasis and drug resistance are still the major problems for breast cancer. Emerging evidence suggest the existence of cancer stem cells (CSCs), a population of cells with the capacity to self-renew, differentiate and be capable of initiating and sustaining tumor growth. In addition, CSCs are believed to be responsible for cancer recurrence, anticancer drug resistance, and metastasis. Hence, compounds targeting breast CSCs may be better therapeutic agents for treating breast cancer and control recurrence and metastasis. Naturally occurring compounds, mainly phytochemicals have gained immense attention in recent times because of their wide safety profile, ability to target heterogeneous populations of cancer cells as well as CSCs, and their key signaling pathways. Therefore, in the present review article, we summarize our current understanding of breast CSCs and their signaling pathways, and the phytochemicals that affect these cells including curcumin, resveratrol, tea polyphenols (epigallocatechin-3-gallate, epigallocatechin), sulforaphane, genistein, indole-3-carbinol, 3, 3′-di-indolylmethane, vitamin E, retinoic acid, quercetin, parthenolide, triptolide, 6-shogaol, pterostilbene, isoliquiritigenin, celastrol, and koenimbin. These phytochemicals may serve as novel therapeutic agents for breast cancer treatment and future leads for drug development.
Use of immunotherapy in recent years has revolutionized cancer treatment for certain types of cancers. However, the broad utility of immunotherapy is limited because there are still many types of ...cancer that do not respond effectively. Failure of a cancer to respond is due, at least in part, to its phenotypic plasticity, a feature that is established by cancer stem cells (CSC) and their associated microenvironments. This article discusses the current understanding of CSC-mediated immune evasion and provides a prospective view on how researchers can better understand and overcome the intrinsic immune privilege of CSCs and the extrinsic immune-suppressive microenvironment shaped by them.
Homogeneous Functionalization of Methane Gunsalus, Niles Jensen; Koppaka, Anjaneyulu; Park, Sae Hume ...
Chemical reviews,
07/2017, Letnik:
117, Številka:
13
Journal Article
Recenzirano
One of the remaining “grand challenges” in chemistry is the development of a next generation, less expensive, cleaner process that can allow the vast reserves of methane from natural gas to augment ...or replace oil as the source of fuels and chemicals. Homogeneous (gas/liquid) systems that convert methane to functionalized products with emphasis on reports after 1995 are reviewed. Gas/solid, bioinorganic, biological, and reaction systems that do not specifically involve methane functionalization are excluded. The various reports are grouped under the main element involved in the direct reactions with methane. Central to the review is classification of the various reports into 12 categories based on both practical considerations and the mechanisms of the elementary reactions with methane. Practical considerations are based on whether or not the system reported can directly or indirectly utilize O2 as the only net coreactant based only on thermodynamic potentials. Mechanistic classifications are based on whether the elementary reactions with methane proceed by chain or nonchain reactions and with stoichiometric reagents or catalytic species. The nonchain reactions are further classified as CH activation (CHA) or CH oxidation (CHO). The bases for these various classifications are defined. In particular, CHA reactions are defined as elementary reactions with methane that result in a discrete methyl intermediate where the formal oxidation state (FOS) on the carbon remains unchanged at −IV relative to that in methane. In contrast, CHO reactions are defined as elementary reactions with methane where the carbon atom of the product is oxidized and has a FOS less negative than −IV. This review reveals that the bulk of the work in the field is relatively evenly distributed across most of the various areas classified. However, a few areas are only marginally examined, or not examined at all. This review also shows that, while significant scientific progress has been made, greater advances, particularly in developing systems that can utilize O2, will be required to develop a practical process that can replace the current energy and capital intensive natural gas conversion process. We believe that this classification scheme will provide the reader with a rapid way to identify systems of interest while providing a deeper appreciation and understanding, both practical and fundamental, of the extensive literature on methane functionalization. The hope is that this could accelerate progress toward meeting this “grand challenge.”
Heat shock factor 1 (HSF1) is a stress-inducible transcription factor and has been described as a multi-faceted modulator of tumorigenesis. Heat shock, accumulation of misfolded proteins, or ...malignant transformation promotes the activation and nuclear translocation of HSF1, where it binds to the promoters of heat shock proteins and an array of nonheat shock-regulated proteins to upregulate their transcription. These stress-responsive and tumor-promoting genes in turn alter the ability of tumor cells to respond to a variety of stresses and enable them to thrive in less than favorable growth conditions. Although a direct role for HSF1 in promoting mRNA transcription of tumor-promoting genes has been suggested, it appears that this property is context- and cell-type dependent. Furthermore, recent studies have demonstrated a direct involvement of mTOR signaling in regulating HSF1-mediated transcription, thus establishing a direct link between protein translation and HSF1 activity. Interestingly, there is a growing understanding of the signaling pathways that are modulated by HSF1 in a variety of tumor types and the co-option of these survival pathways by HSF1 to promote tumorigenesis. This review will focus on the role of HSF1 in protein homeostasis and HSF1-mediated oncogenic signaling pathways that together promote tumorigenesis.
Despite the incredible progress that has been made against cancer over the last few decades, the demographic trends in the United States predict that we will see significant increases in cancer ...incidence and mortality by the year 2030. This, coupled with an aging cancer workforce, would suggest that we will have major challenges ahead in dealing with the increasing burden from cancer. Clearly a critical part of our strategy must be to focus on cancer prevention and control (CPC) efforts and not solely rely on treatment to mitigate this concerning trend. This review discusses how the University of Kansas Cancer Center has had a longstanding emphasis on CPC and has leveraged this expertise to enhance the effectiveness and impact of our community outreach and engagement efforts.
Expression of functional breast cancer susceptibility gene 1 (BRCA1) in human breast and ovarian cancers is associated with resistance to platinum-based chemotherapeutics and poly(ADP ribose) ...polymerase (PARP) inhibitors. BRCA1 is a nuclear tumor suppressor that is critical for resolving double-strand DNA breaks (DSBs) and interstrand crosslinks (ICLs) by homologous recombination (HR). In vitro, animal and human clinical data have demonstrated that BRCA1-deficient cancers are highly sensitive to ICL-inducing chemotherapeutic agents, are amenable to synthetic lethal approaches that exploit defects in DSB/ICL repair, and may be associated with improved survival. Conversely, high or restored expression of BRCA1 in breast and ovarian cancer is associated with therapeutic resistance and poor prognosis. There has been much interest in identifying agents that interfere with BRCA1-dependent DSB/ICL repair to restore or enhance sensitivity to cancer therapeutics. We demonstrate that the heat-shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin 17-AAG (Tanespimycin), currently in Phase II/III clinical evaluation for several cancers, induces BRCA1 ubiquitination and proteasomal degradation, resulting in compromised repair of ionizing radiation- and platinum-induced DNA damage. We show that loss of HSP90 function abolishes BRCA1-dependent DSB repair and that BRCA1-deficient cells are hypersensitive to 17-AAG due to impaired Gap 2/Mitosis (G2/M) checkpoint activation and resultant mitotic catastrophe. In summary, we document an upstream HSP90-dependent regulatory point in the Fanconi anemia/BRCA DSB/ICL repair pathway, illuminate the role of BRCA1 in regulating damage-associated checkpoint and repair responses to HSP90 inhibitors, and identify BRCA1 as a clinically relevant target for enhancing sensitivity in refractory and/or resistant malignancies.
Metastasis is a major cause of cancer-related deaths. A dearth of preclinical models that recapitulate the metastatic microenvironment has impeded the development of therapeutic agents that are ...effective against metastatic disease. Because the majority of solid tumors metastasize to the lung, we developed a multicellular lung organoid that mimics the lung microenvironment with air sac-like structures and production of lung surfactant protein. We used these cultures, called primitive lung-in-a-dish (PLiD), to recreate metastatic disease using primary and established cancer cells. The metastatic tumor-in-a-dish (mTiD) cultures resemble the architecture of metastatic tumors in the lung, including angiogenesis. Pretreating PLiD with tumor exosomes enhanced cancer cell colonization. We next tested the response of primary and established cancer cells to current chemotherapeutic agents and an anti-VEGF antibody in mTiD against cancer cells in two-dimensional (2D) or 3D cultures. The response of primary patient-derived colon and ovarian tumor cells to therapy in mTiD cultures matched the response of the patient in the clinic, but not in 2D or single-cell-type 3D cultures. The sensitive mTiD cultures also produced significantly lower circulating markers for cancer similar to that seen in patients who responded to therapy. Thus, we have developed a novel method for lung colonization
, a final stage in tumor metastasis. Moreover, the technique has significant utility in precision/personalized medicine, wherein this phenotypic screen can be coupled with current DNA pharmacogenetics to identify the ideal therapeutic agent, thereby increasing the probability of response to treatment while reducing unnecessary side effects. SIGNIFICANCE: A lung organoid that exhibits characteristics of a normal human lung is developed to study the biology of metastatic disease and therapeutic intervention.
Survival and replication of most bacteria require the ability to synthesize the amino acid l -tryptophan whenever it is not available from the environment. In this article we describe the genes, ...operons, proteins, and reactions involved in tryptophan biosynthesis in bacteria, and the mechanisms they use in regulating tryptophan formation. We show that although the reactions of tryptophan biosynthesis are essentially identical, gene organization varies among species—from whole-pathway operons to completely dispersed genes. We also show that the regulatory mechanisms used for these genes vary greatly. We address the question—what are some potential advantages of the gene organization and regulation variation associated with this conserved, important pathway?
BRCA1-No Matter How You Splice It Li, Dan; Harlan-Williams, Lisa M; Kumaraswamy, Easwari ...
Cancer research (Chicago, Ill.),
05/2019, Letnik:
79, Številka:
9
Journal Article
Recenzirano
Odprti dostop
(breast cancer 1, early onset), a well-known breast cancer susceptibility gene, is a highly alternatively spliced gene.
alternative splicing may serve as an alternative regulatory mechanism for the ...inactivation of the
gene in both hereditary and sporadic breast cancers, and other
-associated cancers. The alternative transcripts of
can mimic known functions, possess unique functions compared with the full-length
transcript, and in some cases, appear to function in opposition to full-length
In this review, we will summarize the functional "naturally occurring" alternative splicing transcripts of
and then discuss the latest next-generation sequencing-based detection methods and techniques to detect alternative
splicing patterns and their potential use in cancer diagnosis, prognosis, and therapy.
Breast cancer is the most common malignancy in women, and is both pathologically and genetically heterogeneous, making early detection and treatment difficult. A subset of breast cancers express ...normal levels of REST (repressor element 1 silencing transcription factor) mRNA but lack functional REST protein. Loss of REST function is seen in ~ 20% of breast cancers and is associated with a more aggressive phenotype and poor prognosis. Despite the frequent loss of REST, little is known about the role of REST in the molecular pathogenesis of breast cancer.
TCGA data was analyzed for the expression of REST target genes in breast cancer patient samples. We then utilized gene knockdown in MCF-7 cells in the presence or absence of steroid hormones estrogen and/ progesterone followed by RNA sequencing, as well as chromatin immunoprecipitation and PCR in an attempt to understand the tumor suppressor role of REST in breast cancer.
We show that REST directly regulates CEMIP (cell migration-inducing and hyaluronan-binding protein, KIAA1199) and MMP24 (matrix metallopeptidase 24), genes known to have roles in invasion and metastasis. REST knockdown in breast cancer cells leads to significant upregulation of CEMIP and MMP24. In addition, we found REST binds to RE-1 sites (repressor element-1) within the genes and influences their transcription. Furthermore, we found that the estrogen receptor (ESR1) signaling pathway is activated in the absence of REST, regardless of hormone treatment.
We demonstrate a critical role for the loss of REST in aggressive breast cancer pathogenesis and provide evidence for REST as an important diagnostic marker for personalized treatment plans.
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