Understanding EGFR Signaling in Breast Cancer and Breast Cancer Stem Cells: Overexpression and Therapeutic Implications

Epidermal growth factor receptors (EGFRs/HERs) and downstream signaling pathways have been implicated in the pathogenesis of several malignancies including breast cancer and its resistance to treatment with chemotherapeutic drugs. Consequently, several monoclonal antibodies as well as small molecule inhibitors targeting these pathways have emerged as therapeutic tools in the recent past. However, studies have shown that utilizing these molecules in combination with chemotherapy has yielded only limited success. This review describes the current understanding of EGFRs/HERs and associated signaling pathways in relation to development of breast cancer and responses to various cancer treatments in the hope of pointing to improved prevention, diagnosis and treatment. Also, we review the role of breast cancer stem cells (BCSCs) in disease and the potential to target these cells.     

The Histone Acetylation Modifications of Breast Cancer and their Therapeutic Implications

The histone acetylation modifications (HAMs) influence a large number of cellular functions. They are mediated through histone acetyltransferase (HAT) and histone deacetylase (HDAC). Nowadays, people have realized that HAMs are crucial for development and prognosis of breast cancer. Investigations about abnormal HAMs in breast cancer focus on initiating molecular mechanisms in breast cancer development, identification of new biomarkers to predict breast cancer aggressiveness and the therapeutic potential. As HAMs are reversible, breast cancer may be treated by restoring HAMs to normal levels. Indeed, some HDAC inhibitors have been approved by the US Food and Drug Administration to treat certain cancers. Furthermore, HAT inhibitors, HAT activators and HDAC activators may also be used as drugs to treat breast cancer.     

Genetic Heterogeneity in Breast Cancer Susceptibility

Approximately 20% of breast cancer patients have a family history of the disease, and in one-fourth of these cases breast cancer appears to be inherited as an autosomally dominant trait. Five genes and gene regions involved in breast cancer susceptibility have been uncovered. Germ-line mutations in the recently cloned BRCA1 gene at 17q21 is considered to be responsible for the disease in a majority of the breast-ovarian cancer families and in 40-45% of the site-specific breast cancer families, but appears not to be involved in families with both male and female breast cancer cases. The BRCA2 locus at 13q12-q13 appears to be involved in 40-45% of the site-specific breast cancer families, and in most of the families with affected males. The gene located in this region, however, does not seem to confer susceptibility to ovarian cancer. The TP53 gene is involved in breast cancer development in the Li-Fraumeni syndrome and Li-Fraumeni syndrom-like families, whereas germ-line mutations in the androgen receptor (AR) gene is present in a subset of male breast cancers. Furthermore, females who are obligate carriers of ataxia telangiectasia (AT) have a 4-12 times relative risk of developing breast cancer as compared with the general female population, indicating that germ-line mutations in AT also confer susceptibility to breast cancer.     

Intratumoral Heterogeneity in Breast Cancer: A Comparison of Primary and Metastatic Breast Cancers

Intratumoral heterogeneity presents challenges in the management of cancer. To gain deeper insight in intratumoral heterogeneity at different levels and tumor sites for common biomarkers in breast cancers, this report examines seven cases of invasive breast cancer with multiple axillary nodal metastases and/or recurrences for immunohistochemical expression of estrogen receptors, progesterone receptors, human epidermal growth receptor 2, and Ki67 on all tissue blocks in both primary and metastatic tumors.     

Molecular Heterogeneity of Triple-Negative Breast Cancer

Triple-negative breast cancers (TNBCs) are a group of aggressive breast cancers with a greater incidence of relapse, stage-for-stage, than ER/PR-positive and HER2-positive breast cancers, despite optimum loco-regional and systemic therapy. To date, no single targeted therapy has been approved for treatment of TNBC, and cytotoxic chemotherapy remains the standard systemic treatment. Recently, gene expression analysis identified six distinct TNBC subtypes, each with unique biology. In this review we discuss current and forthcoming therapeutic strategies and novel approaches to targeted treatment of these TNBC subtypes.     

Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer

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Detection of VIP Receptors in MNU-Induced Breast Cancer in Rats: Implications for Breast Cancer Targeting

Vasoactive intestinal peptide (VIP) is a 28 amino acid neuropeptide with a wide range of biological activities. Receptors for VIP (VIP-R) are overexpressed in breast cancer, where they may have diagnostic and therapeutic implications. Although N-methyl nitrosourea (MNU)-induced breast cancer in rats is used extensively as a model to study mammary carcinogenesis, there is no information about the expression of VIP-R in this model. Therefore, the purpose of this study was to investigate the presence of VIP-R in MNU-induced breast cancer in rats so that this model can be used to perform studies involving VIP-R. Breast cancer was induced in 36-day-old virgin female Sprague-Dawley rats, by a single intravenous injection of MNU (50mg/kg body weight). The breast tumors were detected 100–150 days after injection. The normal and cancerous rat breast tissue were excised and 20 sections were incubated with 40nM fluorescein-labeled VIP (Fluo-VIP^TM), in the presence and absence of 1000-fold excess unlabeled VIP, pituitary adenylate cyclase activating polypeptide (PACAP) or secretin. The sections were visualized under a fluorescence microscope and photographed. Fluo-VIP^TM stained rat breast cancer tissue homogeneously and to a much greater extent than normal rat breast tissue (p<0.05). This staining was specific as indicated by displacement of Fluo-VIP^TM by excess unlabeled VIP and PACAP. Displacement of Fluo-VIP^TM by secretin indicated the probable presence of VIP receptors of type VPAC1 (VIP receptor subtype1) in the rat breast. These data suggest that, as in human breast cancer, VIP-R, predominantly of type VPAC1, are overexpressed in MNU-induced rat breast cancer tissue as compared to the normal rat breast tissue. Thus, MNU-induced rat breast cancer model can be used as a tool to study the functional role of VIP-R in human mammary carcinogenesis and VIP-R mediated active breast cancer targeting. This could have implications in the diagnosis, prognosis and therapy of human breast cancer.     

Colorectal Cancer Stem Cells: Biology and Therapeutic Implications

The hypothesis that cancer is driven by a subpopulation of tumor-initiating or cancer stem cells (CSC), defined by their selective ability for extensive self-renewal and capacity to give rise to nontumorigenic cancer cell progeny through differentiation, has been validated experimentally in diverse human malignancies. Translational relevance of the CSC hypothesis is underlined by emerging novel strategies designed to target all subpopulations within a given tumor in order to effect cancer eradication and improve patient outcomes. Colorectal cancer stem cells (CRSCs) have been identified and successfully isolated by several research groups based on distinct cell-surface marker characteristics. Identification of CRSC populations has led to a wave of discoveries describing novel self-renewal and drug resistance mechanisms in colorectal cancer that represent novel future therapeutic targets. In this review, we will discuss emerging CRSC-specific pathways and the therapeutic promise of targeting this cancer population in colorectal cancer patients.     

乳腺癌干细胞的调控及作用

乳腺癌是威胁妇女健康的重要疾病之一,由于其病因尚不完全清楚,目前还没有确切的预防方法,手术和放化疗是其主要的治疗办法,但其风险大且具有一定不良反应。研究发现,从实体肿瘤中分离出来的具有自我更新和多向分化能力的乳腺癌干细胞,能够介导肿瘤的侵入、转移和复发等过程,并且能够抵抗传统的放化疗,这对研究以乳腺癌干细胞为靶点的治疗方法具有重要的理论价值和实践意义。本文对乳腺癌干细胞的调控及作用的最新进展作一综述。     

New Therapeutic Targets in Inflammatory Breast Cancer

Inflammatory breast cancer (IBC) is the most lethal variant of locally advanced breast cancer. Although recognized as a distinct clinical entity, there have been few advances in the development of pre-clinical models of IBC, and a lack of IBC-specific therapeutic targets translated into clinical utility to increase overall survival, which is currently 40?% at three years. By use of newly developed pre-clinical models of IBC and patient tumor tissues, E-cadherin, anaplastic lymphoma kinase (ALK), and HSP90 have been identified as targets relevant to IBC that are matched by therapeutics that are either currently in clinical trials or will be tested in clinical trials within the next year. These exciting results illustrate the advances that have been made in recent years in defining the molecular basis of IBC as a distinct disease and the significant strides made in identifying more effective strategies for treatment of patients with IBC.     

Breast Cancer Heterogeneity: Need to Review Current Treatment Strategies

Although the heterogeneity of breast cancer has long been recognized, the hierarchical organization and existence of tumor initiating subpopulation within breast tumors was not known until the last decade. These tumor initiating cells called cancer stem cells (CSCs) display features of stem cells such as unlimited ability to self-renew and lineage differentiation. Accumulating evidence now suggests that by virtue of their relative resistance to both radiation and chemotherapy, these cells contribute to resistance and relapse following therapy. Utilizing cell cultures and mouse xenograft models, we and others demonstrated that breast CSCs have far greater invasive and metastatic potential than differentiated tumor cells which comprise the tumor bulk. Altogether, these studies suggest that targeting and elimination of breast CSCs may be required to improve patient outcome. In this review, we will discuss recent developments in breast CSC research and advances in CSC specific targeted therapies that are in preclinical and clinical trials.     

Biomarkers of Therapeutic Resistance in Breast Cancer

Despite improvements in early detection and adjuvant treatment, a significant fraction of women with early stage breast cancer will eventually develop a recurrence. While improvement in outcomes in metastatic disease has been achieved with new therapeutic options almost all patients eventually develop tumor progression due to drug resistance. We review the mechanisms of resistance to commonly used endocrine, chemotherapeutic, and targeted agents in breast cancer and the interplay of the biomarkers therein.     

自噬与肿瘤发生及治疗抵抗的相关研究进展

自噬是细胞通过溶酶体降解损伤的细胞器和蛋白,维持细胞内物质和能量平衡的途径。自噬在肿瘤发生发展的不同阶段扮演不同角色：肿瘤发生早期抑制细胞恶性转化,进展期维持或促进肿瘤生长。肿瘤治疗抵抗与压力诱导自噬水平改变有关,自噬抑制剂的应用或将成为肿瘤治疗的新手段。     

Long Non Coding RNA in Triple Negative Breast Cancer: A Promising Biomarker in Tumorigenesis

Globally, Triple-negative breast cancer (TNBC) is an unsurpassed variant of breast cancer (BC) with a very high fatality rate, and disease burden. Nevertheless, the deficit of diagnostic markers and focused treatment are major hurdles for potent therapeutics. They are also the reason for bad outcomes and causes of a worse prognosis and a high rate of flare up in patients with TNBC diagnosis. Long non-coding RNAs (lncRNA) are a new class of molecules that have recently gained interest in healthcare management due to their potential as biomarkers for human diseases especially cancers. The growing interest in lncRNA in clinical practice has created an unmet need for developing assays to test lncRNA quickly and accurately for early diagnostics. These lncRNA modulate multiple stages of tumor development, including growth, proliferation, invasion, angiogenesis, and metastases, by controlling several genes and changing metabolic networks. Highly invasive phenotype and chemo resistance are prominent characteristics of TNBC subtypes that require accurate diagnostic and prognostic instruments involving lncRNA. This review focusses on the evolving purpose and coalition of lncRNAs in TNBC and accentuates their capable effects in diagnosis and treatment of cancer. Moreover, the extensive literature analysis of our review creates an opportunity in the translational application concerning the TNBC lncRNAs described until now. The depiction of lncRNAs enrolled in TNBC is comprehensive, and sufficient substantiation studies are the need of the hour to authenticate the current outcomes and create imminent upcoming of elemental research setting into clinical practice.     

Implications of Functional Proteomics in Breast Cancer

Breast cancer is one of the major public health problems of the Western world. Recent advances in genomics and gene expression‐profiling approaches have enriched our understanding of this heterogeneous disease. However, progress in functional proteomics in breast cancer research has been relatively slow. Allied with genomics, the functional proteomics approach will be important in improving diagnosis through better classification of breast cancer and in predicting prognosis and response to different therapies, including chemotherapy, hormonal therapy, and targeted therapy. In this review, we will present functional proteomic approaches with a focus on the recent clinical implications of utilizing the reverse‐phase protein array platform in breast cancer research.