Showing papers by "Aamir Ahmad published in 2013"

Overview of cancer stem cells (CSCs) and mechanisms of their regulation: implications for cancer therapy.

Abstract: The identification of small subpopulations of cancer stem cells (CSCs) from blood mononuclear cells in human acute myeloid leukemia (AML) in 1997 was a landmark observation that recognized the potential role of CSCs in tumor aggressiveness. Two critical properties contribute to the functional role of CSCs in the establishment and recurrence of cancerous tumors: their capacity for self-renewal and their potential to differentiate into unlimited heterogeneous populations of cancer cells. These findings suggest that CSCs may represent novel therapeutic targets for the treatment and/or prevention of tumor progression, since they appear to be involved in cell migration, invasion, metastasis, and treatment resistance-all of which lead to poor clinical outcomes. The identification of CSC-specific markers, the isolation and characterization of CSCs from malignant tissues, and targeting strategies for the destruction of CSCs provide a novel opportunity for cancer research. This overview describes the potential implications of several common CSC markers in the identification of CSC subpopulations that are restricted to common malignant diseases, e.g., leukemia, and breast, prostate, pancreatic, and lung cancers. The role of microRNAs (miRNAs) in the regulation of CSC function is also discussed, as are several methods commonly used in CSC research. The potential role of the antidiabetic drug metformin- which has been shown to have effects on CSCs, and is known to function as an antitumor agent-is discussed as an example of this new class of chemotherapeutics.

Perspectives on new synthetic curcumin analogs and their potential anticancer properties

Abstract: Curcumin is the active component of dried rhizome of Curcuma longa, a perennial herb belonging to ginger family, cultivated extensively in south and southeastern tropical Asia. It is widely consumed in the Indian subcontinent, south Asia and Japan in traditional food recipes. Extensive research over last few decades has shown that curcumin is a potent anti-inflammatory agent with powerful therapeutic potential against a variety of cancers. It suppresses proliferation and metastasis of human tumors through regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases and other enzymes. It induces apoptotic cell death and also inhibits proliferation of cancer cells by cell cycle arrest. Pharmacokinetic data has shown that curcumin undergoes rapid metabolism leading to glucuronidation and sulfation in the liver and excretion in the feces, which accounts for its poor systemic bioavailability. The compound has, therefore, been formulated and administered using different drug delivery systems such as liposomes, micelles, polysaccharides, phospholipid complexes and nanoparticles that can overcome the limitation of bioavailability to some extent. Attempts to avoid rapid metabolism of curcumin until now have been met with limited success. This has prompted researchers to look for new synthetic curcumin analogs in order to overcome the drawbacks of limited bioavailability and rapid metabolism, and gain efficacy with reduced toxicity. In this review we provide a summarized account of novel synthetic curcumin formulations and analogs, and the recent progress in the field of cancer prevention and treatment.

Targeted regulation of Pi3K/Akt/mTOR/NF-κB signaling by indole compounds and their derivatives: Mechanistic details and biological implications for cancer therapy

Abstract: Indole compounds, found in cruciferous vegetables, are potent anti-cancer agents. Studies with indole-3-carbinol (I3C) and its dimeric product, 3,3'-diindolylmethane (DIM) suggest that these compounds have the ability to deregulate multiple cellular signaling pathways, including PI3K/Akt/mTOR signaling pathway. These natural compounds are also effective modulators of downstream transcription factor NF-κB signaling which might help explain their ability to inhibit invasion and angiogenesis, and the reversal of epithelial-to-mesenchymal transition (EMT) phenotype and drug resistance. Signaling through PI3K/Akt/mTOR and NF-κB pathway is increasingly being realized to play important role in EMT through the regulation of novel miRNAs which further validates the importance of this signaling network and its regulations by indole compounds. Here we will review the available literature on the modulation of PI3K/Akt/mTOR/NF-κB signaling by both parental I3C and DIM, as well as their analogs/derivatives, in an attempt to catalog their anticancer activity.

Inhibition of Hedgehog signaling sensitizes NSCLC cells to standard therapies through modulation of EMT-regulating miRNAs

Abstract: Background: Epidermal growth factor receptor- tyrosine kinase inhibitors (EGFR-TKIs) benefit Non-small cell lung cancer (NSCLC) patients, and an EGFR-TKIi erlotinib, is approved for patients with recurrent NSCLC. However, resistance to erlotinib is a major clinical problem. Earlier we have demonstrated the role of Hedgehog (Hh) signaling in Epithelial-to-Mesenchymal transition (EMT) of NSCLC cells, leading to increased proliferation and invasion. Here, we investigated the role of Hh signaling in erlotinib resistance of TGF-β1-induced NSCLC cells that are reminiscent of EMT cells. Methods: Hh signaling was inhibited by specific siRNA and by GDC-0449, a small molecule antagonist of G protein coupled receptor smoothened in the Hh pathway. Not all NSCLC patients are likely to benefit from EGFR-TKIs and, therefore, cisplatin was used to further demonstrate a role of inhibition of Hh signaling in sensitization of resistant EMT cells. Specific pre- and anti-miRNA preparations were used to study the mechanistic involvement of miRNAs in drug resistance mechanism. Results: siRNA-mediated inhibition as well as pharmacological inhibition of Hh signaling abrogated resistance of NSCLC cells to erlotinib and cisplatin. It also resulted in re-sensitization of TGF-β1-induced A549 (A549M) cells as well the mesenchymal phenotypic H1299 cells to erlotinib and cisplatin treatment with concomitant up-regulation of cancer stem cell (CSC) markers (Sox2, Nanog and EpCAM) and down-regulation of miR-200 and let-7 family miRNAs. Ectopic up-regulation of miRNAs, especially miR-200b and let-7c, significantly diminished the erlotinib resistance of A549M cells. Inhibition of Hh signaling by GDC-0449 in EMT cells resulted in the attenuation of CSC markers and up-regulation of miR-200b and let-7c, leading to sensitization of EMT cells to drug treatment, thus, confirming a connection between Hh signaling, miRNAs and drug resistance. Conclusions: We demonstrate that Hh pathway, through EMT-induction, leads to reduced sensitivity to EGFR-TKIs in NSCLCs. Therefore, targeting Hh pathway may lead to the reversal of EMT phenotype and improve the therapeutic efficacy of EGFR-TKIs in NSCLC patients.

Pathways to breast cancer recurrence.

Abstract: Breast cancer remains a deadly disease, even with all the recent technological advancements Early intervention has made an impact, but an overwhelmingly large number of breast cancer patients still live under the fear of “recurrent” disease Breast cancer recurrence is clinically a huge problem and one that is largely not well understood Over the years, a number of factors have been studied with an overarching aim of being able to prognose recurrent disease This paper attempts to provide an overview of our current knowledge of breast cancer recurrence and its associated challenges Through a survey of the literature on cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT), various signaling pathways such as Notch/Wnt/hedgehog, and microRNAs (miRNAs), we also examine the hypotheses that are currently under investigation for the prevention of breast cancer recurrence

Redox cycling of endogenous copper by thymoquinone leads to ROS-mediated DNA breakage and consequent cell death: putative anticancer mechanism of antioxidants.

Abstract: Plant-derived dietary antioxidants have attracted considerable interest in recent past for their chemopreventive and cancer therapeutic abilities in animal models. Thymoquinone (TQ) is the major bioactive constituent of volatile oil of Nigella sativa and has been shown to exert various pharmacological properties, such as anti-inflammatory, cardiovascular, analgesic, anti-neoplastic, anticancer and chemopreventive. Although several mechanisms have been suggested for the chemopreventive and anticancer activity of TQ, a clear mechanism of action of TQ has not been elucidated. TQ is a known antioxidant at lower concentrations and most of the studies elucidating the mechanism have centered on the antioxidant property. However, recent publications have shown that TQ may act as a prooxidant at higher concentrations. It is well known that plant-derived antioxidants can switch to prooxidants even at low concentrations in the presence of transition metal ions such as copper. It is well established that tissue, cellular and serum copper levels are considerably elevated in various malignancies. Copper is an important metal ion present in the chromatin and is closely associated with DNA bases, particularly guanine. Using human peripheral lymphocytes and comet assay, we first show that TQ is able to cause oxidative cellular DNA breakage. Such a DNA breakage can be inhibited by copper-chelating agents, neocuproine and bathocuproine, and scavengers of reactive oxygen species. Further, it is seen that TQ targets cellular copper in prostate cancer cell lines leading to a prooxidant cell death. We believe that such a prooxidant cytotoxic mechanism better explains the anticancer activity of plant-derived antioxidants.

Novel strategies targeting cancer stem cells through phytochemicals and their analogs

Abstract: Cancer stem cells (CSCs) are cells that exist within a tumor with a capacity of self-renewal and an ability to differentiate, giving rise to heterogeneous populations of cancer cells. These cells are increasingly being implicated in resistance to conventional therapeutics and have also been implicated in tumor recurrence. Several cellular signaling pathways including Notch, Wnt, phosphoinositide-3-kinase–Akt–mammalian target of rapamycin pathways, and known markers such as CD44, CD133, CD166, ALDH, etc. have been associated with CSCs. Here, we have reviewed our current understanding of self-renewal pathways and factors that help in the survival of CSCs with special emphasis on those that have been documented to be modulated by well characterized natural agents such as curcumin, sulforaphane, resveratrol, genistein, and epigallocatechin gallate. With the inclusion of a novel derivative of curcumin, CDF, we showcase how natural agents can be effectively modified to increase their efficacy, particularly against CSCs. We hope that this article will generate interest among researchers for further mechanistic and clinical studies exploiting the cancer preventive and therapeutic role of nutraceuticals by targeted elimination of CSCs.

Erlotinib resistance in lung cancer: current progress and future perspectives.

Abstract: Lung cancer is the most common cancer in the world. Despite modern advancements in surgeries, chemotherapies, and radiotherapies over the past few years, lung cancer still remains a very difficult disease to treat. This has left the death rate from lung cancer victims largely unchanged throughout the past few decades. A key cause for the high mortality rate is the drug resistance that builds up for patients being currently treated with the chemotherapeutic agents. Although certain chemotherapeutic agents may initially effectively treat lung cancer patients, there is a high probability that there will be a reoccurrence of the cancer after the patient develops resistance to the drug. Erlotinib, the epidermal growth factor receptor (EGFR)-targeting tyrosine kinase inhibitor, has been approved for localized as well as metastatic non-small cell lung cancer where it seems to be more effective in patients with EGFR mutations. Resistance to erlotinib is a common observation in clinics and this review details our current knowledge on the subject. We discuss the causes of such resistance as well as innovative research to overcome it. Evidently, new chemotherapy strategies are desperately needed in order to better treat lung cancer patients. Current research is investigating alternative treatment plans to enhance the chemotherapy that is already offered. Better insight into the molecular mechanisms behind combination therapy pathways and even single molecular pathways may help improve the efficacy of the current treatment options.

Breast cancer metastasis and drug resistance

Abstract: Among U.S. women, breast cancer is the most commonly diagnosed cancer (excluding skin cancers) and the second leading cause of cancer death, following lung cancer. In 2012, an estimated 226,870 new cases of invasive breast cancer and 39,510 breast cancer deaths are expected to occur among U.S. women. Breast cancer rates vary largely by race/ethnicity and socioeconomic status (SES), and geographic region. Death rates are higher in African American women than in whites, despite their lower incidence rates. Historically, breast cancer was recognized as a disease of western countries. However, over the past 20 years, breast cancer incidence and mortality rates have been increasing rapidly in economically less developed regions. According to 2008 GLOBOCAN estimates, half of the new worldwide breast cancer cases (1.38 million) and 60 % of the breast cancer deaths (458,000) occurred in developing countries. This chapter reviews breast cancer incidence and mortality patterns among women in the U.S. and worldwide, and the possible explanations for these patterns.

Targeting CSCs in Tumor Microenvironment: The Potential Role of ROS-Associated miRNAs in Tumor Aggressiveness

Abstract: Reactive oxygen species (ROS) have been widely considered as critical cellular signaling molecules involving in various biological processes such as cell growth, differentiation, proliferation, apoptosis, and angiogenesis. The homeostasis of ROS is critical to maintain normal biological processes. Increased production of ROS, namely oxidative stress, due to either endogenous or exogenous sources causes irreversible damage of bio-molecules such as DNA, proteins, lipids, and sugars, leading to genomic instability, genetic mutation, and altered gene expression, eventually contributing to tumorigenesis. A great amount of experimental studies in vitro and in vivo have produced solid evidence supporting that oxidative stress is strongly associated with increased tumor cell growth, treatment resistance, and metastasis, and all of which contribute to tumor aggressiveness. More recently, the data have indicated that altered production of ROS is also associated with cancer stem cells (CSCs), epithelial-to-mesenchymal transition (EMT), and hypoxia, the most common features or phenomena in tumorigenesis and tumor progression. However, the exact mechanism by which ROS is involved in the regulation of CSC and EMT characteristics as well as hypoxia- and, especially, HIF-mediated pathways is not well known. Emerging evidence suggests the role of miRNAs in tumorigenesis and progression of human tumors. Recently, the data have indicated that altered productions of ROS are associated with deregulated expression of miRNAs, suggesting their potential roles in the regulation of ROS production. Therefore, targeting ROS mediated through the deregulation of miRNAs by novel approaches or by naturally occurring anti-oxidant agents such as genistein could provide a new therapeutic approach for the prevention and/or treatment of human malignancies. In this article, we will discuss the potential role of miRNAs in the regulation of ROS production during tumorigenesis. Finally, we will discuss the role of genistein, as a potent anti-tumor agent in the regulation of ROS production during tumorigenesis and tumor development.

Antioxidant function of isoflavone and 3,3'-diindolylmethane: are they important for cancer prevention and therapy?

Abstract: Significance: Oxidative stress has been mechanistically linked with aging and chronic diseases, including cancer. In fact, oxidative stress status, chronic disease-related inflammation, and cancer occurred in the aging population are tightly correlated. It is well known that the activation of nuclear factor kappa B (NF-κB) plays important roles in oxidative stress, inflammation, and carcinogenesis. Therefore, targeting NF-κB is an important preventive or therapeutic strategy against oxidative stress, inflammation, and cancer. Recent Advances: A variety of natural compounds has been found to reduce oxidative stress through their antioxidant activity. Among them, isoflavone, indole-3-carbinol (I3C), and its in vivo dimeric compound 3,3′-diindolylmethane (DIM) have shown their promising effects on the inhibition of NF-κB with corresponding reduction of oxidative stress. Critical Issues: It has been found that isoflavone, I3C, and DIM could inhibit cancer development and progression by regulating mul...

The Prooxidant Action of Dietary Antioxidants Leading to Cellular DNA Breakage and Anticancer Effects: Implications for Chemotherapeutic Action Against Cancer

Abstract: Plant-derived dietary antioxidants have attracted considerable interest in recent past for their ability to induce apoptosis and regression of tumors in animal models. While it is believed that the antioxidant properties of these agents may contribute to lowering the risk of cancer induction by impeding oxidative injury to DNA, it could not account for apoptosis induction and chemotherapeutic observations. In this article, we show that dietary antioxidants can alternatively switch to a prooxidant action in the presence of transition metals such as copper. Such a prooxidant action leads to strand breaks in cellular DNA and growth inhibition in cancer cells. Further, the cellular DNA breakage and anticancer effects were found to be significantly enhanced in the presence of copper ions. Moreover, inhibition of antioxidant-induced DNA strand breaks and oxidative stress by Cu(I)-specific chelators bathocuproine and neocuproine demonstrated the role of endogenous copper in the induction of the prooxidant mechanism. Since it is well established that tissue, cellular, and serum copper levels are considerably elevated in various malignancies, such a prooxidant cytotoxic mechanism better explains the anticancer activity of dietary antioxidants against cancer cells.

Deregulation of PI3K/Akt/mTOR signaling pathways by isoflavones and its implication in cancer treatment.

Abstract: Cancer remains a difficult disease to manage because of the deregulation of numerous signaling pathways that are associated with its development and progression. One such pathway is the phosphoinositide 3-kinase (PI3K) - protein kinase B (Akt) - mammalian target of rapamycin (mTOR) signaling network, which is known to be associated with poor prognosis in many human cancers. Targeted inhibition of this signaling network in vitro, in vivo and in clinics has suggested this to be an effective strategy for the inhibition of cancer cells' proliferation and metastases. Towards this end, the use of natural agents for therapeutic intervention has attracted renewed interest because of their non-toxic effects as well as their ability to modulate multiple pathways. Investigations involving isoflavones have suggested a potent anticancer activity of these compounds against multiple factors in the PI3K/Akt/mTOR pathway. In addition to their use as therapeutic agents against various cancers, there is evidence to support the role of isoflavones in potentiation of radiation therapy as well as the anticancer action of other conventional therapeutic drugs. In this review article, we discuss our current understanding of the regulation of PI3K/Akt/mTOR signaling pathways by isoflavones, which could be responsible for their observed in vitro and in vivo activity against human cancers.

3, 3′-diindolylmethane Enhances the Effectiveness of Herceptin against HER-2/Neu-Expressing Breast Cancer Cells

Abstract: Herceptin failure is a major clinical problem in breast cancer. A subset of breast cancer patients with high HER-2/neu levels eventually experience metastatic disease progression when treated with Herceptin as a single agent. Mechanistic details of development of this aggressive disease are not clear. Therefore, there is a dire need to better understand the mechanisms by which drug resistance develops and to design new combined treatments that benefit patients with aggressive breast cancer and have minimal toxicity. We hypothesized that 3, 3′-diindolylmethane (DIM), a non-toxic agent can be combined with Herceptin to treat breast cancers with high levels of HER-2/neu. Here, we evaluated the effects of Herceptin alone and in combination with DIM on cell viability, apoptosis and clonogenic assays in SKBR3 (HER-2/neu-expressing) and MDA-MB-468 (HER-2/neu negative) breast cancer cells. We found that DIM could enhance the effectiveness of Herceptin by significantly reducing cell viability, which was associated with apoptosis-induction and significant inhibition of colony formation, compared with single agent treatment. These results were consistent with the down-regulation of Akt and NF-kB p65. Mechanistic investigations revealed a significant upregulation of miR-200 and reduction of FoxM1 expression in DIM and Herceptin-treated breast cancer cells. We, therefore, transfected cells with pre-miR-200 or silenced FoxM1 in these cells for understanding the molecular mechanism involved. These results provide experimental evidence, for the first time, that DIM plus Herceptin therapy could be translated to the clinic as a therapeutic modality to improve treatment outcome of patients with breast cancer, particularly for the patients whose tumors express high levels of HER-2/neu.

Stem Cells and Cancer

Abstract: It is widely accepted that cancers arise from cancer stem cells that possess self-renewal capacity and can recapitulate the tumors derived from it. However, the cellular origin of cancers is not clear. Emerging evidence is accumulating showing that cancers of distinct subtypes within an organ may derive from different “cell of origin.” Cancer stem cells may originate from long-lived normal stem cells, transit amplifying progenitor cells or more committed differentiated cells through different mechanisms by which cancer cells acquire unlimited self-renewal capacity. The identification of these crucial target cell populations may allow earlier detection for the prevention of malignancies, and it may also provide targets that could be exploited for eventual elimination of cancers with aggressive phenotype.

Perspectives on the role of isoflavones in prostate cancer.

Abstract: Isoflavones have been investigated in detail for their role in the prevention and therapy of prostate cancer. This is primarily because of the overwhelming data connecting high dietary isoflavone intake with reduced risk of developing prostate cancer. A number of investigations have evaluated the mechanism(s) of anticancer action of isoflavones such as genistein, daidzein, biochanin A, equol, etc., in various prostate cancer models, both in vitro and in vivo. Genistein quickly jumped to the forefront of isoflavone cancer research, but the initial enthusiasm was followed by reports on its contradictory prometastatic and tumor-promoting effects. Use of soy isoflavone mixture has been advocated as an alternative, wherein daidzein can negate harmful effects of genistein. Recent research indicates a novel role of genistein and other isoflavones in the potentiation of radiation therapy, epigenetic regulation of key tumor suppressors and oncogenes, and the modulation of miRNAs, epithelial-to-mesenchymal transition, and cancer stem cells, which has renewed the interest of cancer researchers in this class of anticancer compounds. This comprehensive review article summarizes our current understanding of the role of isoflavones in prostate cancer research.

Targeting MicroRNAs for Personalized Cancer Therapy

Abstract: and CD24 –/lo have aberrant expression of miRNAs and much greater self-renewal activity, proliferation and tumor initiation than other cancer cells. The high expression of miR-21, miR-181a and miR-181b has been observed in breast CSCs; however, these cells express very low levels of let-7, miR-34, miR-200, miR-29, miR-30a and miR-93. Similar to breast CSCs, prostate CSCs express a very low level of miR-34, which targets AR and CD44 expression. Therefore, both breast and prostate CSCs have a high expression of CD44. However, prostate CSCs express low levels of other miRNAs, different from those expressed by breast CSCs. The expression of miR-320 and miR-708 is significantly downregulated in prostate CSCs, unlike in breast CSCs. Molecular mechanistic studies show that miR-320 and miR-708 could inhibit tumor formation from CSCs by targeting β-catenin or Introduction

The role of cancer stem cells and miRNAs in defining the complexities of brain metastasis.

Abstract: Researchers and clinicians have been challenged with the development of therapies for the treatment of cancer patients whose tumors metastasized to the brain. Among the most lethal weapons known today, current management of brain metastases involves multiple therapeutic modalities that provide little, if any, for improving the quality of life and overall survival. Recently the role of cancer stem cells (CSCs) in the development of cancer has been studied extensively, and thus its role in the prognosis, diagnosis, and treatment is now being investigated even in the realm of brain metastasis. Recognizing the molecular make-up of CSCs as well as understanding the role of these cells in resistance to treatment modalities is expected to benefit cancer patients. Additionally, past decade has witnessed an increase in awareness and understanding of the role of microRNAs (miRNAs) in various cancer types, and the deregulation miRNAs are critically important for the regulation of genes during the development and progression of human malignancies. The role miRNAs in brain metastasis is being investigated, and has also shown tremendous promise for future research. In this review, we discuss the problem and lethality of brain metastases and the current state of management, and further provide insight into novel avenues that are worth considering including the biological complexities of CSCs and miRNAs for designing novel therapies.

Lung Cancer Stem Cells: Current Progress and Future Perspectives

Abstract: Cancer stem cells (CSCs) have attracted a lot of interest in the field of cancer research in recent years. Lung CSCs share many characteristics with the normal pluripotent stem cells, such as self-renewal and multi-potent abilities. Identification of normal adult lung stem cells and their response to injury has led us to the lung cancer stem cells, partially based on the knowledge that lung CSCs as well as the normal lung stem cells share similar markers and/or location in the airway tree. Several studies have identified CD133, CD44, ALDH (aldehyde dehydrogenase) and ABCG2 (ATP-binding cassette sub-family G member 2) as lung cancer stem cell markers, all of which are validated CSC markers in multiple other cancer types as well. Embryogenesis signaling pathways, such as the hedgehog, wnt and notch pathways has also been implicated as determinants of lung CSC phenotype. With the central role of CSCs in tumor recurrence, metastasis and drug-resistance, targeting CSC markers and/or signaling pathways to eradicate lung cancer and enhance patient outcome is an attractive approach. This review summarizes our current understanding of CSC markers and signaling pathways in lung cancer.

Current Understanding of Drug Resistance Mechanisms and Therapeutic Targets in HER2 Overexpressing Breast Cancers

Abstract: A subset of breast cancers is marked by overexpression of HER2 receptor and activated HER2-mediated signaling. Targeting HER2 offers a unique therapeutic approach for the treatment of such breast cancers. Trastuzumab, lapatinib, and, more recently, pertuzumab, have been approved by FDA to treat HER2 overexpressing breast cancers. Although the drugs effectively target HER2 leading to a favorable clinical response in patients initially, a majority of patients turn refractory to HER2 targeted drugs as early as within a year of administration. Trastuzumab, being the first HER2 targeted drug, has been investigated in detail in relation to acquired resistance, and emerging reports are evident for such drug resistance in lapatinib treated HER2 overexpressing breast cancers as well. This chapter takes a look at the progress of treatment options in HER2 overexpressing breast cancers with focus on mechanisms that are believed to be responsible for drug resistance. We also discuss the current strategies being investigated to overcome drug resistance.

MicroRNAs in Breast Cancer Research: Progress and Promise

Abstract: Over the years, remarkable progress has been made in regards to our understanding of breast cancer biology and consequently the development of novel treatments. One idea that has proven to be immensely valuable is the use of microRNAs (miRNAs) in cancer diagnosis, prognosis, and even for treatment. The miRNAs are short RNA molecules that are able to post-transcriptionally regulate the expression of genes at multiple levels. Past and current research has continued to classify miRNAs as either highly or rarely expressed in cancer cells in relation to their normal non-cancerous counterparts. This classification is also used to organize the various miRNAs as either tumor suppressing or oncogenic. For example, aberrant expression of certain miRNAs is widely accepted to signify different stages of cancer. This chapter summarizes our current understanding of the role of miRNAs in cancer, while enlightening the readers with the role of specific miRNAs in breast cancer development and progression, and their exploitation for designing innovative therapeutic strategies.

The Biology of the Deadly Love Connection Between Obesity, Diabetes, and Breast Cancer

Abstract: Breast cancer is the most common malignant disease of women in the world and a leading cause of women’s deaths. Many risk factors such as genetics, hormones, aging, and environment have been associated with breast cancer. Interestingly, a large number of epidemiological and clinical studies suggest that obesity and diabetes, especially type-2 diabetes, are associated with higher risk of breast cancer. Similarly, these chronic diseases, such as obesity, diabetes, and cancer, are also a major public health concern in the world. Fifty percent of the United States’ population is overweight, thirty percent is obese, and ten percent has diabetes mellitus. Therefore, obesity and diabetes mellitus have been considered as potential risk factors for many cancers but this chapter is focused only on breast cancer. Although the mechanisms responsible for the development of these chronic diseases leading to the development of breast cancer are not fully understood, the biological importance of the activation of insulin, insulin like growth factor-1 (IGF-1) and its receptor (IGF-1R) signaling pathways in insulin-resistance mechanism and subsequent induction of compensatory hyperinsulinemia has been proposed. Therefore, targeting insulin/IGF-1 signaling with anti-diabetic drugs for lowering blood insulin levels and reversal of insulin-resistance could be a useful strategy for the prevention and/or treatment of breast cancer. Increased numbers of clinical studies have demonstrated that the administration of commonly used anti-diabetic drugs such as metformin decreases the risk of cancers, suggesting that these agents might be useful anti-tumor agents for the treatment of breast cancer. In this chapter, we will discuss the potential roles of anti-diabetic drug metformin as anti-tumor agents in the context of breast cancer, and will further discuss the potential roles of microRNAs (miRNAs) in the pathogenesis of obesity, diabetes, and breast cancer.

Metal-based anticancer agents: targeting androgen-dependent and androgen-independent prostate and COX-positive pancreatic cancer cells by phenanthrenequinone semicarbazone and its metal complexes

Abstract: A planar, polycyclic and aromatic hydrocarbon ligand, namely 9,10-phenanthrenequinone semicarbazone, and its transition metal complexes have been synthesized and structurally characterized. The in vitro antiproliferative activity of these compounds against five human cancer cell lines revealed that they were effective against androgen receptor-positive/negative prostate cancer cells as well as COX-positive pancreatic BxPC-3 cancer cell line. The driving force behind such antiproliferative activity seems to be the up-regulated COX expression in these cells, which was amenable for targeting through metal complexation. These structural motifs can, therefore, serve as a starting point for developing novel cytotoxic agents against the growing number of prostate and pancreatic cancers.

Resistance and DNA Repair Mechanisms of Cancer Stem Cells: Potential Molecular Targets for Therapy

Abstract: Cancer stem cells (CSCs) are small subpopulations of cells within tumors that are intricately related to both de novo and acquired resistance to conventional therapies leading to tumor recurrence and metastasis. A majority of cancers initially respond to chemotherapeutic agents, as well as radiation therapy, but eventually develop resistance. An increased understanding of CSCs has led to the discovery that current treatments target the differentiated cancer cells leaving the CSCs unscathed due to their robust signaling pathways. Further, maintenance of genomic fidelity is important for normal functioning and survival of cells, including cancer cells and the CSCs. In this chapter, we will discuss several such pathways/phenomena which help CSCs resist therapies. These include increased quiescence and up-regulated drug transporters, activated DNA repair mechanisms and activation of several key cellular signaling pathways (Fig. 3.1). A better understanding of these resistance pathways is a necessary prerequisite towards the ultimate goal of developing novel strategies specifically targeting CSCs. Better designed therapies could ultimately reverse their resistance and thereby eliminate the potential of tumor recurrence and metastasis.

The Complexities of Racial Disparity in Breast Cancer

Abstract: Breast cancer is one of the most common types of cancers as well as a leading cause of cancer-related deaths in women in the United States. Although there has been a recent decline in breast cancer mortality, certain ethnic groups continue to suffer from higher mortality rates. The causes of racial disparities in breast cancer patients are still unclear, but understanding the molecular mechanism(s) and associated factors that may contribute to racial disparity will help in improving the treatment outcome of patients in such minority groups in the future. The disparity in breast cancer statistics between African American (AA) women and European American (EA) women has particularly been a topic of much discussion and investigation. Previous studies have focused on breast cancer mortality rates, but more recent studies are addressing the racial and ethnic disparities specific to breast cancer. In the future, a deeper understanding of the racial disparities in breast cancer will lead to improved cancer preventative care, diagnosis and treatment. Here, we summarize the social factors that are known to contribute to racial disparity in breast cancer.

Abstract 5327: Upregulation of miR-10b associated with breast cancer metastasis to brain .

Abstract: Background: Breast cancer is the most common non-skin cancer amongst women in the US. Breast cancer-related mortality is primarily due to metastatic disease, especially brain metastasis which also impacts patient9s quality of life. The molecular mechanism of brain metastasis of breast cancer is largely unknown; however, finding molecular signatures of the primary breast cancer that have the propensity for brain metastasis would be very important for designing optimal primary treatment of breast cancer to prevent and eliminate brain metastasis. To that end targeting MicroRNAs (miRNAs) could become a novel prognostic and therapeutic strategy to prevent the future development of brain metastasis. Design: Breast cancer cases with brain metastasis diagnosed from 1994-2011 were retrieved from the computerized hospital database. The study cohort comprised of breast cancer cases with brain metastasis (n=18) and age, stage and follow-up matched breast cancer cases without brain metastasis (n= 10). All cases were microscopically reviewed to select tumor blocks with >50% tumor cells. RNA was extracted from formalin fixed paraffin embedded tumor tissue blocks. The miRNA expression analysis was done using RT-PCR. Data was statistically analyzed to determine the clinical significance using the Wilcoxon signed rank test. Results: Among several miRNAs that were analyzed in this study, we found that miR-10b was highly expressed in the primary breast cancer specimens of patients who subsequently developed brain metastasis compared to those who did not develop brain metastasis. Interestingly, the expression of miR-10b was reduced in brain metastatic specimens compared to primary breast cancer specimens. Using Wilcoxon signed rank test, there was statistically significant difference between the paired tumors from breast cancers and brain metastasis (p value Conclusions: Increased expression of miR-10b appears to be associated with metastatic potential of the primary breast cancer; however, once the cancer metastasized to the brain (homing), its level was reduced. This interesting finding requires further mechanistic studies. Clinical relevance: Our findings are clinically very relevant since miR-10b could serve as a potential target for anti-metastatic therapy. The expression of miR-10b could be silenced using miR-10b antagomirs (chemically modified anti-miRNA oligonucleotides) for the prevention of brain metastasis, whereas once brain metastasis develops then it could be treated with miR-10b mimics for inducing its expression for the treatment. Therefore, development of miRNA-based prophylactic therapies could serve as personalized medicine against future brain metastasis of breast cancer which will improve patients’ quality of life and improve overall survival. Citation Format: Seema Sethi, Aamir Ahmad, Sandeep Mittal, Rouba Ali, Wei Chen, Fazlul H. Sarkar. Upregulation of miR-10b associated with breast cancer metastasis to brain . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5327. doi:10.1158/1538-7445.AM2013-5327

Epigenetic Regulations of mRNAs and miRNAs by Nutraceuticals

Abstract: Both genetic alterations and epigenetic regulations of genes could lead to the development of human cancers. However, recent studies have shown that epigenetic alteration contributes significantly not only to the development of cancer but also responsible for the progression of cancer to metastatic disease. The epigenetic regulations of specific genes in human cancer cells include DNA methylation, acetylation, histone modification, nucleosome remodeling, and small non-coding RNA regulation including the regulation of microRNAs (miRNAs). Among many epigenetic regulations, DNA methylation is the most common event and has been well studied for understanding the mechanisms of epigenetic regulation of genes. The DNA hypermethylation occurs in the promoter sequences of tumor suppressor gene or tumor suppressive miRNAs leading to the down-regulation in the expression of tumor suppressor mRNAs or miRNAs, resulting in the development and progression of various cancers. Interestingly, recent studies have shown that several non-toxic natural agents known as nutraceuticals including isoflavone, curcumin, (−)-epigallocatechin-3-gallate, resveratrol, indole-3-carbinol, 3,3′-diindolylmethane, and lycopene could demethylate DNA at their hypermethylation sites or modulate histone, demonstrating their potential roles in the epigenetic regulation of mRNAs and miRNAs. These epigenetic regulations of mRNAs and miRNAs could be one of the molecular mechanisms by which nutraceuticals inhibit carcinogenesis and cancer progression, and thus either nutraceuticals or their synthetic analogs could serve as novel demethylating agents for the treatment of human malignancies.