Emerging roles of haemostatic proteins as markers of disease progression and prognosis in breast cancer

The role of radiation therapy in the management of primary breast cancer

Breast Cancer in the Asia–Pacific Region

Over the last two decades we have seen a number of important advances in the biological underpinnings of breast cancer that have had a significant impact either directly or indirectly on the management and ultimately on the prognostic outcome of this disease. First, we now know that breast cancer is a heterogeneous disease made up of a number of unique subtypes each with its own natural history and associated prognostic outcome [1]. Second, some of these subtypes have specific targets (including ER and HER2) that have associated unique targeted therapeutic agents that significantly impact the natural history of this disease [2]. Third, data indicate that these targets are not static with approximately 30% of tumors showing discordance in the expression of hormone receptor or HER2 between the primary and associated metastatic tumor [3]. The therapeutic implications of such discordance have understandably resulted in most oncologists seeking to biopsy metastatic sites whenever possible. Despite these advances we have a long way to go with current research focusing on looking for biomarkers that have a dual prognostic and predictive function. An ideal biomarker being one able to accurately predict for early recurrence or progression of disease, provide information to guide therapeutic decisions, reliably predict response to specific treatment, provide an easy platform for testing of markers such as ER and HER2 at various time points along a cancer history continuum, and allow for the identification of unique targets that would help specific drug development. Circulating tumor cells (CTCs) is one such biomarker that has been actively investigated over the last decade and has shown promising results in a number of malignancies including breast cancer. The presence of epithelial cells in the circulation that are similar in appearance to primary tumor cells was first described by TR Ashworth about 150 years ago in a woman with metastatic breast cancer [4]. These detectable cancer cells are CTCs that represent a rare cell population in the circulation usually representing less than 10 cells/ml. These cells can originate from either the primary or metastatic tumor tissue and require special enrichment techniques for their detection [5]. These techniques are based either on the biological properties of the CTCs such as protein secretion or cell surface antigen expression or are based on the physical characteristics of these cells such as presence of electric charges, size of the cell, density or deformability. Currently the only FDA approved CTC enumeration Using circulating tumor cells to guide therapy in breast cancer: could this replace biopsies?

Estrogens Determine Adherens Junction Organization and E-Cadherin Clustering in Breast Cancer Cells via Amphiregulin.

Adjuvant therapy of primary breast cancer. 4th International Conference on Adjuvant Therapy of Primary Breast Cancer St. Gallen, Switzerland.

Breast cancer is the most common cancer and the second leading cause of cancer death in American women. It was the second most common cancer in the world in 2002, with more than 1 million new cases. Despite advances in early detection and the understanding of the molecular bases of breast cancer biology, about 30% of patients with early-stage breast cancer have recurrent disease. To offer more effective and less toxic treatment, selecting therapies requires considering the patient and the clinical and molecular characteristics of the tumor. Systemic treatment of breast cancer includes cytotoxic, hormonal, and immunotherapeutic agents. These medications are used in the adjuvant, neoadjuvant, and metastatic settings. In general, systemic agents are active at the beginning of therapy in 90% of primary breast cancers and 50% of metastases. However, after a variable period of time, progression occurs. At that point, resistance to therapy is not only common but expected. Herein we review general mechanisms of drug resistance, including multidrug resistance by P-glyucoprotein and the multidrug resistance protein family in association with specific agents and their metabolism, emergence of refractory tumors associated with multiple resistance mechanisms, and resistance factors unique to host-tumor-drug interactions. Important anticancer agents specific to breast cancer are described.

Metastatic breast cancer has high rates of relapse and mortality. The absence of definitive prognostic biomarker and effective therapeutic target is the major obstacle to end this aggressive disease. Epigenetic dysregulation plays a crucial role in breast cancer metastasis. However, the mechanism by which epigenetic dysregulation stimulates the hypoxia-mediated breast cancer progression and metastasis remains unknown. Based on luciferase reporter assays and analysis of expression changes of 720 epigenetic genes in three microarray datasets, we identified epigenetic reader ZMYND8 as a novel hypoxia-inducible factor (HIF) target gene. Human breast cancer tissue microarray data indicated that ZMYND8 is highly expressed in invasive breast tumors and this overexpression is significantly correlated with poor clinical outcomes in patients with breast cancer. ZMYND8 depletion dramatically attenuates the tumorigenic potential of breast cancer cells in colony formation, migration and invasion in vitro, and suppresses breast tumor growth and metastasis in mice. To elucidate the underlying mechanism, we performed co-immunoprecipitation, chromatin immunoprecipitation and quantitative PCR assays and found that ZMYND8 interacts with HIF complex and acetyl lysine 16 of histone H3 at the hypoxia inducible elements (HREs) to provoke the expression of HIF target genes LOX, AGR2, AQP1 and VEGFA. ZMYND8 controls breast cancer growth and metastasis through HIF in mice. We further found that p300 binds and acetylates ZMYND8 in breast cancer cells. Acetylated ZMYND8 interacts with and recruits BRD4 to the HREs to stimulate RNA polymerase II phosphorylation, thereby promoting transcriptional elongation of HIF target genes. ZMYND8 acetylation is necessary and sufficient for breast tumor growth and metastasis in vitro and in mice. Together, p300-ZMYND8-BRD4-HIF axis is critical for breast cancer progression and metastasis. In summary, ZMYND8 represents a positive feedback mechanism that amplifies HIF-mediated breast cancer progression and metastasis, and provides a potential epigenetic target for the prognosis and treatment of breast cancer. Citation Format: Yan Chen, Bo Zhang, Lei Bao, Lai Jin, Mingming Yang, Yan Peng, Jennifer Wang, Chenliang Wang, Xuan Zou, Yingfei Wang, Weibo Luo. Epigenetic reader ZMYND8 bridges BRD4 and hypoxia-inducible factors to mediate breast cancer progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 82.

Section 1.- Role of Modeling in Pharmacotherapeutics.- Section 2.- PET and Nuclear Medicine Imaging of the Breast.- Functional Radiologic Imaging in Breast Cancer.- Section 3.- Prevention of Breast Cancer.- Section 4.- DCIS: Pathology and Molecular Markers.- Ductal Carcinoma In Situ: a Modern Approach to Patient Management.- Ductal Carcinoma In Situ: Systemic Treatment.- Section 5.- Tailored Surgery for Early Breast Cancer: Surgical Techniques.- Tailored Surgery for Early Breast Cancer: Biological Aspects.- Tailored Surgery for Early Breast Cancer: the Very Young Woman.- Tailored Surgery for Older Women with Breast Cancer.- Section 6.- Tailored Radiotherapy for Breast Cancer Stages I and II: Technical Aspects.- Breast Cancer Management in the Era of Molecular Medicine: Tailored Radiotherapy - Clinical and Biological Aspects.- Early Breast Cancer (Stage I and II): Tailored Radiotherapy for Very Young Women.- The Elderly and Breast Cancer Radiotherapy.- Section 7.- Early Breast Cancer (Stage I and Stage II): Tailored Systemic Therapy for Endocrine-Resistant Breast Cancer.- Early Breast Cancer (Stage I and Stage II): Tailored Systemic Therapy for Endocrine-Responsive Breast Cancer.- Tailored Therapy for Breast Cancer in Very Young Women.- Tailored Systemic Therapy for the Elderly Woman.- Section 8.- Locoregional Therapy Following Neoadjuvant Chemotherapy: an Evolving Paradigm of Treatment Individualization.- Medical Therapy of Locally Advanced Breast Cancer.- Section 9.- Metastatic Breast Cancer: Tailored Endocrine Therapy for Premenopausal Women.- Metastatic Breast Cancer: Tailored Endocrine Therapy for Postmenopausal Women.- Metastatic Breast Cancer: Tailored Chemotherapy for the Elderly Woman.- Section 10.- Treatment of Brain Metastases from Breast Cancer.- Surgical Management of Breast Cancer Liver Metastases.- Individualization of Bisphosphonate Therapy.- Breast Cancer Metastases to the Eye.- Organ-Specific Approaches: Pain Management.- Section 11.- Genomic and Molecular Classification of Breast Cancer.- Applications of Proteomics to Clinical Questions in Breast Cancer.- Section 12.- Targeting the HER Family of Receptors in the Treatment of Advanced Breast Cancer.- Biological Therapies for Metastatic Breast Cancer: Antiangiogenesis.- Breast Cancer Gene Therapy.- Innovative Rational-Derived, Target-Based and Cytotoxic Therapies for Breast Cancer and Other Malignancies.- Section 13.- Mechanisms of Breast Cancer Resistance to Chemotherapy.- Mechanisms of Resistance to Hormone Therapy.- Novel Signaling Pathways in Breast Cancer.- Mechanisms of Apoptosis Resistance In Breast Cancer.- Section 14.- Breast Cancer and Pregnancy.- Hormone Replacement Therapy After Breast Cancer.- Male Breast Cancer.- Patients' Preferences: What Makes Treatments Worthwhile?.- Breast Cancer: the Impact of Depression and its Treatment.- Molecular Profiling in Breast Cancer.- Clinical Trials in the Era of Treatment Tailoring.

Advances in Screening, Diagnosis, and Treatment of Breast Cancer

Breast cancer is the most common cause of cancer death among women worldwide. Therapeutic decisions in breast cancer are based on stage and specific tumour characteristics. In addition to conventional imaging and histopathological evaluation, potentially non-invasive molecular imaging of tumour metabolism (by means of the [18F] fluorodeoxyglucose (FDG)-positron emission tomography, FDG-PET) and known predictive biosensitivity, markers (oestrogen-and progesterone receptor, HER2) can be used for disease evaluation in the future. Molecular imaging provides a functional, dynamic aspect that might be useful for diagnostic purposes, treatment selection, and for monitoring treatment response at a molecular level. This is of particular interest in view of the dynamics of tumour metabolism and biomarker expression during progression and treatment of breast cancer. For staging of recurrent and metastatic breast cancer, FDG-PET imaging of tumour metabolism can be of value in selected cases, with its high sensitivity, but varying specificity. For response monitoring and prognostic evaluation, FDG-PET may be useful, but future studies are required to confirm this. Molecular imaging of tumour HER2 and the oestrogen receptor was shown to be feasible in metastatic breast cancer. Imaging of these biomarkers may allow a more tumour specific detection than with FDG-PET or conventional imaging, but its use in breast cancer staging-or treatment requires further evaluation. Future options for molecular imaging in breast cancer include monitoring of other significant biomarkers (such as the progesterone receptor), or direct treatment evaluation by radiolabelling targeted therapeutic drugs (such as the antivascular endothelial growth factor antibody bevacizumab). To establish molecular imaging in practical (breast) cancer care, more extensive research is needed, but clearly the possibilities are extensive.

Despite advances in clinical therapy, metastasis is still the leading cause of death in breast cancer patients. A better understanding of mechanisms that drive metastasis is a prerequisite for new approaches to effectively prevent and inhibit this most dangerous advancement of the disease. While alterations in the nuclear genome are pivotal in oncogenesis, a role of mitochondria in cancer progression has remained largely unexplored. Mutations in mitochondrial DNA are found in breast tumors and other cancers, however their involvement in driving the disease is unclear. Our study identifies mitochondrial complex I as critical for defining an aggressive phenotype in breast cancer cells. Complex I is the gate-keeper of the respiratory chain and catalyzes the first step of NADH oxidation. It elevates the cellular NAD+/NADH ratio and translocates protons across the inner mitochondrial membrane, which ultimately leads to energy production. We used a unique approach to define contributions of mitochondrial complex I activity to breast cancer progression, based on expression of yeast NADH dehydrogenase Ndi1. Ndi1 encodes a single protein that translocates to mitochondrial, faces the inner mitochondrial matrix and oxidizes NADH from the Krebs cycle. Specific enhancement of mitochondrial complex I activity by Ndi1 expression inhibited tumor growth and metastasis through regulation of the tumor cell NAD+/NADH redox balance, mTORC1 activity, and autophagy. Conversely, non-lethal reduction of NAD+ levels by interfering with nicotinamide phosphoribosyltransferase expression to disturb the NAD+ synthesis and recycling pathway, rendered tumor cells more aggressive and increased metastasis. Thus, the results indicate a cause-and-effect relationship between reduced NAD+/NADH ratios and metastatic activity. Having established that enhancement of NAD+/NADH levels by augmenting breast cancer cell complex I activity inhibits tumorigenicity and metastasis, we used this new concept therapeutically and hypothesized that supplementing tumor cell nutrients with NAD+ precursors, such as nicotinic acid (NIC) or nicotinamide (NAM), could interfere with breast cancer progression. We demonstrate that enhancing NAD+ levels through NAD+ precursor treatment effectively inhibits experimental metastasis of human breast cancer cells in xenograft models. Importantly, this treatment also inhibited spontaneous metastasis, and increased animal survival when the therapy was started after surgical removal of primary tumors. Furthermore, NAD+ precursor treatment strongly interferes with oncogene driven breast cancer development and progression in transgenic MMTV-PyMT mice. Thus, aberration in mitochondrial complex I NADH dehydrogenase activity can profoundly enhance the aggressiveness of human breast cancer cells while therapeutic normalization of the NAD+/NADH balance can inhibit metastasis and prevent disease progression. Our study demonstrates that mitochondrial complex I regulation of tumor cell NAD+/NADH levels impacts breast cancer growth and metastasis, and translates into a new therapeutic approach for preventing breast cancer progression. This is highly relevant as current standard of care for cancer patients relies primarily on chemo- and radiation therapies aimed at killing the tumor cells. Evolutionary models predict that selective pressure imposed by these approaches causes survival of resistant clones that eventually re-activate the disease. Based on the central involvement of metabolic tumor cell alterations in cancer, therapeutic normalization of tumor cell metabolism might interfere with the expansion of residual and break-through clones. Thus, a combination of standard therapy with NAD+ precursor treatment may halt breast cancer progression and prevent relapse. Citation Format: Antonio F. Santidrian, Akemi Matsuno-Yagi, Melissa Ritland, Byoung B. Seo1,2, Sarah E. LeBoeuf, Laurie J. Gay, Takao Yagi, Brunhilde Felding-Habermann. Normalizing tumor cell metabolism in breast cancer metastasis: A novel therapeutic approach. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr IA3.

Simple SummaryBreast cancer remains the most commonly diagnosed cancer and the leading cause of cancer death among females worldwide. It is a highly heterogeneous disease, classified according to hormone and growth factor receptor expression. Patients with triple negative breast cancer (TNBC) (estrogen receptor-negative/progesterone receptor-negative/human epidermal growth factor receptor (HER2)-negative) and hormone-independent HER2 overexpressing subtypes still represent highly aggressive behavior, metastasis, poor prognosis, and drug resistance. Thus, new alternative anticancer agents based on the use of natural products have been receiving enormous attention. In this regard, curcumin is a promising lead in cancer drug discovery due its ability to modulate a diverse range of molecular targets and signaling pathways. The current review has emphasized the underlying mechanism of curcumin anticancer action mediated through the modulation of PI3K/Akt/mTOR, JAK/STAT, MAPK, NF-ĸB, p53, Wnt/β-catenin, apoptosis, and cell cycle pathways in hormone-independent breast cancer, providing frameworks for future studies and insights to improve its efficiency in clinical practice.Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women worldwide. Despite the overall successes in breast cancer therapy, hormone-independent HER2 negative breast cancer, also known as triple negative breast cancer (TNBC), lacking estrogens and progesterone receptors and with an excessive expression of human epidermal growth factor receptor 2 (HER2), along with the hormone-independent HER2 positive subtype, still remain major challenges in breast cancer treatment. Due to their poor prognoses, aggressive phenotype, and highly metastasis features, new alternative therapies have become an urgent clinical need. One of the most noteworthy phytochemicals, curcumin, has attracted enormous attention as a promising drug candidate in breast cancer prevention and treatment due to its multi-targeting effect. Curcumin interrupts major stages of tumorigenesis including cell proliferation, survival, angiogenesis, and metastasis in hormone-independent breast cancer through the modulation of multiple signaling pathways. The current review has highlighted the anticancer activity of curcumin in hormone-independent breast cancer via focusing on its impact on key signaling pathways including the PI3K/Akt/mTOR pathway, JAK/STAT pathway, MAPK pathway, NF-ĸB pathway, p53 pathway, and Wnt/β-catenin, as well as apoptotic and cell cycle pathways. Besides, its therapeutic implications in clinical trials are here presented.

Metastatic breast cancer is lethal and incurable. The major obstacle to ending this aggressive disease is the absence of definitive prognostic biomarker and effective therapeutic target. Epigenetic dysregulation plays a crucial role in breast cancer metastasis. However, how epigenetic dysregulation under tumor hypoxia stimulates breast cancer progression and metastasis remains unknown. We recently identified the epigenetic reader ZMYND8 as a novel HIF target gene by analyzing expression changes of 720 epigenetic genes in three microarray gene expression and mRNA sequencing datasets. Analysis of a human breast cancer tissue microarray revealed that ZMYND8 is highly expressed in invasive breast tumors and high levels of ZMYND8 are significantly correlated with poor clinical outcomes in patients with breast cancer. ZMYND8 depletion significantly suppresses colony formation, invasion, and migration of breast cancer cells in vitro, and inhibits breast tumor growth and metastasis in mice. To figure out the underlying mechanism, we performed co-immunoprecipitation, chromatin immunoprecipitation, and quantitative PCR assays and found that ZMYND8 interacts with HIF complex and acetyl lysine 16 of histone H3 at the hypoxia response elements (HREs) to stimulate the expression of HIF target genes LOX, AGR2, AQP1, and VEGFA. HIF is required for ZMYND8-mediated breast cancer growth and metastasis in mice. We further found that p300 binds and acetylates ZMYND8 in breast cancer cells. Acetylated ZMYND8 interacts with the bromodomains of BRD4 and recruits BRD4 to the HREs to stimulate RNA polymerase II phosphorylation and subsequent transcriptional elongation of HIF target genes. ZMYND8 acetylation is necessary and sufficient for breast tumor growth and metastasis in vitro and in mice. Together, these findings indicate that p300-acetylated ZMYND8 mediates breast cancer progression and metastasis by BRD4-dependent activation of HIF. In summary, ZMYND8 represents a positive-feedback mechanism that amplifies HIF-mediated breast cancer progression and metastasis, and may be a potential epigenetic target for the prognosis and treatment of breast cancer. Citation Format: Yan Chen, Bo Zhang, Lei Bao, Lai Jin, Mingming Yang, Yan Peng, Jennifer Wang, Chenliang Wang, Xuan Zou, Yingfei Wang, Weibo Luo. HIF-ZMYND8-BRD4 axis mediates breast cancer progression and metastasis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B52.

LINC00511 is a newly discovered long intergenic nonprotein-coding RNA (Ribonucleic acid) with unknown. Differential gene expression analysis was performed on breast cancer microarray data, and the upregulated expression of LINC00511 in breast cancer tissues and breast cancer cell lines was verified by qRT-PCR (quantitative Reverse Transcription-Polymerase Chain Reaction). A cohort study revealed a correlation between the expression of LINC00511 and the clinicopathological features in breast cancer patients. The effects of LINC00511 on breast cancer migration and invasion were studied in vitro. Then, an experiment using the Illumina Infinium Human Methylation450 Beadchip data was conducted to study the role of DNA (Deoxyribonucleic acid) methylation in LINC00511 expression, and DAVID (Database for Annotation, Visualization and Integrated Discovery) Functional Annotation Bioinformatics Microarray Analysis was used to determine the biological functions and potential pathways of LINC00511 in breast cancer. Then, LINC00511 and key genes associated with breast cancer disease progression were further studied in TCGA (The Cancer Genome Atlas), and western blotting was used to verify the results at the protein level. Finally, we further studied the effect of LINC00511 on Panobinostat drug sensitivity in breast cancer and its effect on the prognosis of breast cancer patients. LINC00511 was upregulated in breast cancer patients. The expression of LINC00511 was closely related to lymph node metastasis, tumor size and molecular subtypes of breast cancer. The in vitro studies revealed that LINC00511 could promote the migration and invasion in MDA-MB-231 and MCF-7 cells. In terms of mechanism, DNA hypomethylation promoted the expression of LINC00511, furthermore LINC00511 promoted the expression of Wnt10A, E2F2, TGFA, and MET, which participate in the progression of breast cancer. In addition, LINC00511 reduced the sensitivity of breast cancer cells to Panobinostat. Moreover, breast cancer patients with a high expression of LINC00511 had a poor prognosis. DNA hypomethylation promotes the expression of LINC00511 in breast cancer, and LINC00511 promotes the progression of breast cancer by upregulating Wnt10A, E2F2, TGFA and MET. High expression of LINC00511 is associated with poor prognosis. Our study identified the mechanism of LINC00511 upregulation and provides novel information on the progression of breast cancer.

Trastuzumab Beyond Progression in Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: UK Practice now and in the Future