Current Drug Targets (v.11, #9)

Despite a recent decline in incidence, breast cancer remains as one of the most frequently diagnosed cancers and the second leading cause of cancer related deaths in American women [1]. There are a number of challenges that impact our ability to effectively treat this disease. First, breast cancer is a heterogeneous collection of diseases that demonstrate diverse histopathologies [2], genomic alterations [3], gene expression patterns [4, 5], clinical features, and therapeutic outcomes [6]. A second major challenge is the lack of treatment options for breast cancers that are inherently resistant or acquire resistance to multiple therapies including cytotoxic, endocrine, and targeted therapies [7-11]. Finally, there is a paucity of treatments that are effective against metastatic breast cancer [12], and thus the majority of patients with metastases will eventually succumb to the disease. Despite these complex issues, the development of targeted therapies such as trastuzumab to treat Her2+ breast cancers [13, 14] and tamoxifen and aromatase inhibitors to treat hormone receptor-positive breast cancers [15] have had a major impact on disease outcome for a significant number of patients. These success stories indicate that additional targeted therapies used in a personalized fashion will allow us to more effectively treat this heterogeneous disease to prevent resistance, recurrence, and ultimately, death due to metastasis. In this special issue ten articles highlight emerging targets that are highly promising for the development of targeted therapies for breast cancer. One recurring theme, targeting breast cancer stem/tumor initiating cells, reflects the explosion of literature in this field during the last 5-10 years. For example, Prosperi and Goss, Pal et al., Greene et al., and Visbal and Lewis, highlight the literature describing the promise and pitfalls of targeting Wnt signaling, miRNAs, Hedgehog signaling, and the Notch pathway to eradicate tumor initiating cells to prevent disease recurrence and metastasis. Tumor initiating cells, and cancer cells in general, also display altered metabolism, and Davison and Schafer discuss the literature focused on targeting metabolic pathways as potential therapeutic targets for breast cancer. In addition to targeting tumor initiating cells, there are several other promising avenues for the development of targeted therapies for breast cancer. One area that has gained a great deal of interest during the last decade is the role of the microenvironment during the growth and progression of breast cancer. Goldberg and Schwertfeger discuss the role of the immune system and specific inflammatory mediators as potential targets for breast cancer. Baxley and Serra describe the TGFand#946; signaling network that plays an important role in mediating cross-talk between breast tumor cells and the microenvironment. This network is also a critical mediator of epithelial to mesenchymal transition, which facilitates breast cancer metastasis. Other key targets that facilitate tumor-microenvironment interactions and metastasis are macrophage stimulating protein (MSP) and its receptor Ron discussed by Kretschmann et al. McHenry and I discuss the Rho GTPase signaling network, which functions to integrate multiple signals from the extracellular environment, as a potential target for treatment of breast cancer. This signaling network, like many of the others highlighted in this issue, has pleiotropic functions. Thus, therapeutics targeting this pathway may have utility in multiple stages and subtypes of breast cancer. Finally, Sachdev describes a number of clinical trials investigating the efficacy of drugs targeting the IGF signaling network. Of all the specific pathways discussed in this issue, the development and testing of drugs targeting this network is most advanced. Over the last decade we have learned a tremendous amount about the cellular and molecular basis of this complex disease. As we continue to unravel the specific pathways that control the growth and progression of tumor cells in specific types of breast cancer, new targets will be identified. I hope you enjoy this special issue showcasing several highly promising targets for breast cancer treatment that are on the horizon.

Rho GTPase signaling is altered in human breast tumors, and elevated expression and activation of Rho GTPases correlate with tumor progression, metastasis, and poor prognosis. Here we review the evidence that Rho signaling functions as a key regulator of cell cycle, mitosis, apoptosis, and invasion during breast cancer growth and progression and discuss whether these pleiotropic actions enhance or limit the targetability of this network. We propose that depending on the stage and subtype of breast cancer, targeting Rho signaling may have chemopreventative, antitumor, and anti-metastatic efficacy. An understanding of how Rho signaling is perturbed in specific stages and subtypes of breast cancer and how it functions in the context of the complex in vivo environment during the stochastic process of tumor formation and progression are necessary in order to effectively target this signaling network for breast cancer treatment.

Small Players With Big Roles: MicroRNAs as Targets to Inhibit Breast Cancer Progression by Stephanie B. Greene, Jason I. Herschkowitz, Jeffrey M. Rosen (1059-1073).
As modulators of gene expression, microRNAs (miRNAs) are essential for normal development. Not surprisingly, aberrant expression of miRNAs is associated with many diseases, including cancer. Studies of various breast cancer subtypes have demonstrated that, like gene expression profiles and pathological differences, miRNA profiles can distinguish various tumor subtypes. Over the last few years, roles for miRNAs during many stages of breast cancer progression have been established. This includes potential breast cancer associated polymorphisms in miRNA target sites or miRNAs themselves, miRNAs that can act as tumor suppressors or oncogenes, and miRNAs that can modulate metastatic spread. Recent studies have also suggested key roles for miRNAs in regulating cancer stem cells. Thus, miRNAs have now become important therapeutic targets. This can be achieved by replacing miRNA expression where it has been lost or decreased, or conversely by inhibiting miRNA expression where it has been amplified or overexpressed in cancers. Ultimately, miRNAs should provide both important prognostic biomarkers as well as new targetable molecules for the treatment of breast cancer.

A Wnt-ow of Opportunity: Targeting the Wnt/β-Catenin Pathway in Breast Cancer by Jenifer R. Prosperi, Kathleen H. Goss (1074-1088).
Aberrant activation of the Wnt/and#946;-catenin signaling pathway is a hallmark of many tumors, including breast cancer. In the normal breast, tightly regulated expression of Wnt/and#946;-catenin pathway components, including Wnts and the APC tumor suppressor, dictates its role in balancing stem cell self-renewal, maintenance and differentiation during embryonic and postnatal development. Therefore, not surprisingly, dysregulation of Wnt/and#946;-catenin signaling through overexpression of pathway activators, such as Wnts or stabilized and#946;-catenin, or targeted disruption of inhibitors, such as APC, leads to mammary tumorigenesis in several genetically engineered mouse (GEM) models. These models are powerful tools to dissect the importance of Wnt/and#946;-catenin signaling in human breast cancer because they recapitulate some of the histological features of human breast cancers that demonstrate pathway dysregulation. Over the last decade, numerous approaches have been developed to target the Wnt/and#946;-catenin pathway in tumor cells, from antagonizing Wnt ligand secretion or binding to promoting and#946;-catenin degradation to specifically blocking and#946;-catenin-mediated transcriptional activity. Despite sizeable hurdles because of gaps in our knowledge of the most efficacious ways to inhibit the pathway, the breast cancer subtypes to target and how pathway antagonists might be used in combination therapy, crippling Wnt/and#946;- catenin signaling offers a tremendous opportunity to impact breast cancer pathogenesis. This review will provide an overview of the current understanding of Wnt/and#946;-catenin pathway involvement in regulating normal breast development and morphogenesis, the generation of Wnt/and#946;-catenin-dependent GEM models of human breast cancer, upregulation of signaling in human breast cancers and the compelling therapeutic strategies aimed at targeting the Wnt/and#946;-catenin pathway that show promising anti-tumor activity.

Inhibiting Breast Cancer Progression by Exploiting TGFβ Signaling by Sarah E. Baxley, Rosa Serra (1089-1102).
Transforming Growth Factor and#946; (TGFand#946;) signaling influences most aspects of cellular function in addition to playing a major role in organ development, remodeling, and repair. Given the wide range of effects induced by TGFand#946;, it is not surprising that alterations in TGFand#946; signaling have been implicated in development and progression of many different cancer types. Within the context of breast cancer itself, TGFand#946; is known to have a dual nature, being both tumorsuppressive during early breast cancer development and tumor-promoting during breast cancer metastasis. Targets for breast cancer therapeutics are greatly needed to decrease morbidity and mortality from this devastating disease. Here, we summarize what is known about TGFand#946; in breast cancer progression and discuss potential TGFand#946; targets for breast cancer therapeutics.

Hedgehog Signaling in the Normal and Neoplastic Mammary Gland by Adriana P. Visbal, Michael T. Lewis (1103-1111).
The hedgehog signal transduction network is a critical regulator of metazoan development. Inappropriate activation of this network is implicated in several different cancers, including breast. Genetic evidence in mice as well as molecular biological studies in human cells clearly indicate that activated signaling can lead to mammary hyperplasia and, in some cases, tumor formation. However, the exact role(s) activated hedgehog signaling plays in the development or progression of breast cancer also remain unclear. In this review, we have discussed recent data regarding the mechanism(s) by which the hedgehog network may signal in the mammary gland, as well as the data implicating activated signaling as a contributing factor to breast cancer development. Finally, we provide a brief update on the available hedgehog signaling inhibitors with respect to ongoing clinical trials, some of which will include locally advanced or metastatic breast cancers. Given the growing intensity with which the hedgehog signaling network is being studied in the normal and neoplastic mammary gland, a more complete understanding of this network should allow more effective targeting of its activities in breast cancer treatment or prevention.

Keeping A Breast of Recent Developments in Cancer Metabolism by Calli A. Davison, Zachary T. Schafer (1112-1120).
For decades, it has been recognized that cancer cells display a unique metabolism; specifically, cancer cells have been shown to preferentially utilize glycolysis instead of mitochondrial respiration. This phenomenon is commonly known as the and#x201C;Warburg effectand#x201D; after Otto Warburg who first made this observation in 1927. The discovery of the Warburg effect has lead to new methods of detection and differentiation of cancerous tissue and normal tissue. More recently, alterations in cancer metabolism have been researched as a possible target for chemotherapeutic intervention in a number of cancers. The push to understand the metabolism of cancer cells has been particularly acute in breast cancer cells, where multiple novel metabolic mechanisms have recently been described and characterized. However, despite this recent progress, the completion of additional studies on the cellular metabolism of breast cancer cells is necessary before drugs that target cancer cell metabolism could be available to disease-afflicted women. Here, we review recent discoveries in breast cancer cell metabolism as well as current logical drug targets that could be used to alter cell metabolism to promote the selective elimination of breast cancer cells.

The insulin-like growth factors (IGFs) acting via the type I IGF receptor (IGF-1R) regulate cancer cell proliferation, survival, metabolism and metastasis. Drugs targeting the IGF-1R are being tested in human clinical trials for cancer therapy and it seems likely that this class of drugs could be approved soon. Recent data suggests that insulin receptor, which is closely related to IGF-1R, should also be targeted to maximally inhibit the system. Furthermore, biomarkers that identify patients whose tumors are driven by IGF-1R and biomarkers that allow monitoring or prediction of response are needed. This article reviews the different drugs against IGF-1R that are being tested and how this receptor pathway can be optimally targeted for cancer therapy with an emphasis on breast cancer therapy.

Inflammation within the tumor microenvironment correlates with increased invasiveness and poor prognosis in many types of cancer, including breast cancer. The cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNFand#945;) and interleukin-1 beta (IL-1and#946;) are critical mediators of the inflammatory response. Numerous studies have also linked these cytokines to breast cancer progression. As a result, the mechanisms by which these cytokines promote breast cancer have been recently explored using both in vitro and in vivo models. The results from these studies have led to speculation regarding the possible usefulness of targeting these cytokines in breast cancer patients. This review summarizes the most recent studies pertaining to the mechanisms by which proinflammatory cytokines promote breast cancer. Furthermore, the possibilities of targeting these inflammatory mediators in breast cancer patients using inhibitors that are currently being used in the clinic for other inflammatory conditions are discussed. Understanding both the mechanisms by which inflammatory mediators promote breast cancer and the effectiveness of anti-inflammatory drugs in treating breast cancer will lead to novel therapeutic regimens to treat this devastating disease.

Targeting the Perpetrator: Breast Cancer Stem Cell Therapeutics by Arindam Pal, Kelli E. Valdez, Martha Z. Carletti, Fariba Behbod (1147-1156).
The hypothesis that tumors may originate from a rare population of cancer stem cells (CSCs) has gained tremendous popularity in recent years and is supported extensively by several pioneering works. Cancer therapies targeting CSCs have unlimited potential for relapse free survival of cancer patients. As a result, knowledge of biological pathways that govern CSCs is very important and this review is focused on the biology of CSCs with special emphasis on breast CSCs, and recent advances in therapeutic approaches targeting them.

Macrophage Stimulating Protein (MSP) is the only known ligand for the receptor tyrosine kinase Ron. The MSP/Ron pathway is involved in several important biological processes, including macrophage activity, wound healing, and epithelial cell behavior. A role for MSP/Ron in breast cancer has recently been elucidated, wherein this pathway regulates tumor growth, angiogenesis, and metastasis. Here, we review the recent literature surrounding MSP/Ron function in tumor cells, inflammatory cells, and osteoclasts - cell types that often coexist in breast tumor microenvironments. We discuss the potential implications of MSP/Ron activity occurring concurrently in these cell types on tumor progression and metastasis. Lastly, we outline the potential for targeting MSP/Ron as a novel therapy for breast cancer, and for other cancer types.

Tyrosine Kinase Receptor Transactivation Associated to G Protein-Coupled Receptors by Vanessa Almendro, Susana Garcia-Recio, Pedro Gascon (1169-1180).
G protein-coupled receptors (GPCRs) comprise a large family of membrane receptors involved in signal transduction. These receptors are linked to a variety of physiological and biological processes such as regulation of neurotransmission, growth, cell differentiation and oncogenesis among others. Some of the effects of GPCRs are known to be mediated by the activation of MAPK pathways. Several GPCRs are also able to transactivate receptors with tyrosine kinase activity (TKR) such as EGFR and HER2 and thus to control DNA synthesis and cell proliferation. The interaction between these receptors not only plays an important physiological role but its disregulation can induce pathological states such as cancer. For this reason, the crosstalk between these two types of receptors can be considered a possible mechanism for cell transformation, tumor progression, reactivation of the metastatic disease, and the acquisition of resistance to therapies targeting TKR receptors. The transactivation of some TKRs by GPCRs is related to the lost of response of TKRs to inhibitors of TK activity, mainly by the activation of the c-Src protein which can directly phosphorylate and activate the cytoplasmic domain of a TKR. For these reason, the dual inhibition of GPCRs and TKRs in some types of cancer has been proposed as a better strategy to kill tumor cells. Increased understanding of the mechanisms that interconnect the two pathways regulated by GPCRs and TKRs may facilitate the design of new therapeutic strategies.

Molecular Targeting of Aberrant Transcription Factors in Leukemia: Strategies for RUNX1/ETO by Christian Wichmann, Manuel Grez, Jorn Lausen (1181-1191).
Malignant cell transformation is caused by mutations in distinct key regulatory genes involved in cell growth, apoptosis, senescence and differentiation. Particularly in human leukemia, chromosomal translocations involving crucial hematopoietic transcription factors are frequently causally linked to the disease. Transcription factors commonly have a modular structure, comprising distinct domains for DNA- binding, dimerization and protein-protein interaction. Each domain is functionally important and in principle accessible for a molecular-based therapeutic intervention. Uncovering the molecular structure of critical domains will allow the rational development of therapeutic agents that inhibit particular functions of leukemogenic transcription factors. However, so far most approaches are in the experimental stage. Among others, the RUNX1/ETO fusion protein, commonly found within acute myeloid leukemia cells carrying the translocation t(8;21), is currently intensively studied at the functional and structural level as well as in animal models. This combined effort has allowed the development of specific targeting approaches addressing different functional domains of the fusion protein. With a special focus on RUNX1/ETO we will discuss recent strategies to directly interfere with aberrant transcription factors to block their leukemogenic function.