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2013-2014 Research Grant Abstracts

The Canadian Breast Cancer Foundation – Prairies/NWT Region has invested over $4.77 million into six different institutions in Alberta, Manitoba and Saskatchewan as part of the 2013/2014 Research Grant Program. Fourteen projects that are focused on research such as developing targeted treatments to customize patient care, advancing risk prediction and reduction or improving methods of diagnosis in order to improve prognosis received funding this year. Click to download the abstracts as a PDF.

University of Saskatchewan – Dr. Francisco Cayabyab

Molecular Switches Promoting HERG Ion Channel Expression in Human Breast Cancers

Breast cancer remains a complex disease process and its incidence is increasing worldwide. Human breast cancer cells can arise when molecular switches in breast tissue become hyperactive, resulting in uncontrolled proliferation. In some cases, hormone replacement therapy has been associated with increased incidence of human breast cancers. The hormone estrogen is a major factor in regulating cell division and proliferation, and promotes gene expression by activating intracellular messengers or switches, including STATs (signal transducer and activator of transcription). Also in recent years, emerging evidence suggest the potassium ion channel called HERG is over-expressed in many types of cancer cells and our pilot studies provide new evidence linking HERG channel over-expression with activation of STATs.

The current study funded by the Canadian Breast Cancer Foundation – Prairies/NWT Region will use cutting-edge imaging technology, biochemical and electrophysiological techniques, and human breast cancer cells to determine how estrogen triggers HERG expression and cancer cell growth to ultimately identify new anti-cancer drug targets that inhibit breast tumors.

University of Alberta – Dr. Sambasivarao Damaraju

Targeted Re-sequencing and Fine Mapping of Breast Cancer Susceptibility Loci at Chromosome 4q31.22 Identified by Genome Wide Association Study

Breast cancer is a complex disease with many subtypes reflecting the heterogeneity at both histological and molecular levels. This is a disease with varied causes, with contributions from genetic, environmental and life style factors. The two major types of breast cancer are familial or hereditary (age of onset <40 years), which comprises 20% of all cases and to some extent determined by the predisposing BRCA mutation in germline DNA, and sporadic (age of onset > 40 years), which is comprised of the remaining cases, yet with little information on genetic predisposition. Recently, Damaraju lab and independent international teams reported progress in the identification of the genetic determinants of breast cancer using whole genome scans.

The current Canadian Breast Cancer Foundation – Prairies/NWT Region funded project is aimed to further characterize these identified genetic variants and help narrow down the gene region conferring risk to gain biological insights; these investigations will also explore the link between genetics and the well known risk factor, body mass index (proxy for obesity). Understanding these relationships may be used to screen populations at risk for breast cancer and develop prophylactic therapeutic interventions.

University of Calgary – Dr. Elise Fear

Monitoring breast treatment progress with novel microwave imaging techniques

Microwave breast imaging creates images with low-power microwaves. Healthy and diseased tissues have different microwave properties and these properties are expected to change in response to treatment of breast disease. These changes may be monitored with different imaging methods, however, there is a need for an inexpensive, patient friendly, efficient and effective method of tracking changes in the breast.

This Canadian Breast Cancer Foundation – Prairies/NWT Region funded project takes a novel approach to microwave breast imaging, designed to establish such a method. This approach involves integrating two different methods, the first maps the general structure of tissues, and the second refines these maps to provide more detail on variations in tissues.

This project will test the new approach on numerical and experimental models that represent changes in the breast while undergoing treatment and then build a microwave scanning system. This project will provide feasibility testing of the new approach to microwave breast imaging for treatment monitoring, as well as a scanning system ready for patient studies.

University of Saskatchewan – Dr. Andrew Freywald

The role of the EphB6 receptor in the regulation of Death Receptor-induced apoptosis in breast cancer

Breast cancer is the second-leading cause of cancer-related death in women. Development of efficient therapies targeting tumour-related molecules is critical for patient survival. The DR4 and DR5 death receptor (DR) proteins are closely related and specifically kill cancer cells, however, their usefulness is limited in breast cancer because of frequent resistance. Identification of DR4- and DR5-controlling mechanisms is crucial for the improvement of breast cancer treatment. Our observations show a cell-surface protein, EphB6, enhances DR5-mediated killing of breast cancer cells. Therefore, EphB6 may represent a promising target for novel therapies, activating EphB6 to improve DR5/DR4-mediated breast cancer elimination.

In this project funded by the Canadian Breast Cancer Foundation – Prairies/NWT Region, the effect of EphB6 on DR-mediated breast cancer elimination will be further characterized and the mechanics of its actions investigated. This work is expected to identify new mechanisms controlling cancer resistance and may trigger the development of novel approaches to effectively treat breast cancer by activating EphB6 to enhance DR-mediated tumour destruction.

University of Manitoba – Dr. Spencer Gibson

Role of lysosome mediated cell death in breast cancer treatment.

Drug resistance is a major problem in treating breast cancer. One strategy to overcome drug resistance is to disrupt the bundle of enzymes called lysosomes. The release of enzymes from lysosomes causes degradation of proteins within cells, leading to cell death. We have discovered the lysosome disruptor induces lysosome rupture and cell death in breast cancer cells. With funding from the Canadian Breast Cancer Foundation – Prairies/NWT Region, this team will further investigate these findings to determine the extent of lysosome disruption in chemotherapy alone or in combination with siramesine.

They will also investigate whether lysosome disruptors inhibit drug resistance in breast cancer cells. The key strategy of this project is to determine the effectiveness of lysosome targeted drugs alone or in combination leading to effective breast cancer treatment.

University of Alberta – Dr. Roseline Godbout

Investigating the role of a protein called DEAD Box 1 (DDX1) in treatment-resistant breast cancer

DEAD box proteins affect a large number of cellular processes as a result of binding to RNA and changing the structure of RNA. Previous work has shown that elevated levels of a DEAD box protein called DDX1 in breast cancer are associated with early recurrence. Importantly, high levels of DDX1 may also predict whether a particular breast cancer patient will respond to chemotherapy or hormone therapy. This Canadian Breast Cancer Foundation – Prairies/NWT Region funded project will focus on investigating how DDX1 functions so that we can understand why some breast cancer patients do not respond to therapy and, as a consequence, suffer early relapse.

This project will use a combination of molecular biology, biochemistry and analysis of breast cancer tissue to investigate the role of DDX1 in breast cancer. The proposed work will form the foundation for future experiments designed to inhibit DDX1 function in breast cancer with the goal of achieving improved response in treatment-resistant patients.

University of Alberta – Dr. Ing Swie Goping

Defining a novel growth pathway that modulates chemotherapeutic resistance in breast cancer

Biomarkers are used to manage the care of cancer patients. “Prognostic biomarkers” indicate the likely course of disease in a patient regardless of therapy. “Predictive biomarkers” identify patients who are most likely to respond to a specific therapy and are the basis of “personalized” medicine. In breast cancer, only two predictive biomarkers are routinely used and they are estrogen/progesterone receptors to predict sensitivity to endocrine therapy and HER2 to predict sensitivity to Trastuzumab/Herceptin treatment. Due to a lack of predictive markers, conventional chemotherapies are not given in a “personalized” manner. To address this gap, this research group found that higher levels of a protein (named “Bad”) were associated with increased survival of breast cancer patients treated with taxane chemotherapy. Therefore, in this Canadian Breast Cancer Foundation – Prairies/NWT Region funded project, the role of Bad in breast cancer will be investigated. This work may lead to the development of a new predictive biomarker for breast cancer.

University of Calgary – Dr. Randal Johnston

Novel Oncolytic Reovirus Platforms with Improved Potency towards Breast Cancer

There is an urgent need for new approaches to cancer therapy, as many tumor varieties remain difficult to treat and side effects from conventional therapy can have consequences that persist for many years. Thus, much attention has been focused on the potential for genetically modified viruses in cancer therapy as certain types of virus can proliferate better in transformed cells than in normal cells, leading to their death and tumour regression. This Canadian Breast Cancer Foundation – Prairies/NWT Region funded project will work to engineer new strains of oncolytic reovirus as a further step in this direction. Reovirus was one of the original viruses identified as a potential cancer therapeutic agent and the original wild-type strain is already in Phase II and III clinical trials for multiple types of cancer. This project is designed to add new activities to the virus that will enable it to be tracked and enhance immune response and breast cancer cell killing.

University of Manitoba – Dr. Thomas Klonisch

Protective role of HMGA2 in triple-negative breast cancer cells

Triple-negative breast cancer (TNBC) is a highly aggressive type of breast cancer with low chemotherapy success rates. Inhibitors of the DNA-damage repair protein PARP1 have shown promising results but sensitivity to PARP inhibitors in breast cancer cells is variable. It has been demonstrated that the DNA-binding/repair molecule and stem cell marker HMGA2 protects cancer cells from cell death upon treatment with DNA damaging drugs. HMGA2 is a marker for poor prognosis for TNBC patients and breast cancer cells positive for HMGA2 are more resistant to chemotherapy. HMGA2 may antagonize the therapeutic success of PARP inhibitors by promoting DNA repair. This Canadian Breast Cancer Foundation – Prairies/NWT Region funded project will determine if eliminating HMGA2 and PARP activity can enhance cell death in TNBC exposed to chemotherapy. It is expected that the inhibition of HMGA2 activity will significantly improve the success rate of PARP inhibitor treatment in TNBC patients.

University of Calgary – Dr. Ki-Young Lee

Regulation of Breast Tumor Cell Proliferation by Neutrophil-Derived APRIL

Breast cancer is the second most common type of cancer after lung cancer. Understanding the molecular mechanism that underlies the uncontrolled growth of cancer cells is crucial for eradicating this devastating disease. A proliferation-inducing ligand (APRIL) has been detected in about 40% of breast cancer tissues examined, and it was determined that this protein originates from neutrophil immune cells in the tumor microenvironment. Our studies revealed that breast cancer cells stimulate neutrophils to secrete APRIL which in turn enhances breast cancer cell proliferation, indicating that APRIL targets specific proteins in breast cancer cells to promote growth. The objectives of this Canadian Breast Cancer Foundation – Prairies/NWT Region funded project are to analyze the signaling mechanism through which APRIL induces breast cancer cell proliferation, and identify and characterize the molecular targets and interactions of APRIL in breast cancer cells. These studies can provide the basis for focusing on APRIL and its targets for the prevention and/or therapy of breast cancer.

University of Alberta – Dr. Raymond Lai

The clinical and biological significance of Sox2 in breast cancer

Cancer cells are known to express proteins that are normally restricted
to the embryonic stem cells, a highly immature cell type, with one such protein being in Sox2. Recently, using a novel molecular tool, it was found that breast cancer cells, even those derived from the same tumor, are biologically dichotomous – having two parts within the cells. Specifically, it was found that a small subset of cells showed evidence of Sox2 activity whereas the majority of the cells lacked Sox2 activity. Importantly, experimental
results have led to the belief that the small subset of cells showing Sox2 activity may represent
the so-called “cancer stem cells”, which are believed to contribute to drug resistance and
cancer relapse.

In this Canadian Breast Cancer Foundation – Prairies/NWT Region funded study, the differential Sox2activity in breast cancer will be tested to determine if it is truly a useful marker which
can further the understanding of the biology of breast cancer to potentially develop new treatment strategies to fight it.

University of Manitoba – Dr. Etienne Leygue

Estrogen receptor beta and SRA/SRAP system: functional interactions in triple negative breast cancer

Studies have shown some tumors contain special molecules or targets that make them vulnerable to existing therapies. For example, if a tumor contains the estrogen receptor alpha (ER), it will respond to tamoxifen and the tumor growth will slow down when treated. Similarly, if a tumor contains HER2, it will be sensitive to Herceptin, an antibody specifically targeting this membrane molecule. Unfortunately, for some tumors, called triple-negative because they do not contain any of the three usual targets, it is difficult to find an efficient treatment. Two new molecules, ER-beta and SRA/SRAP, were recently found that predict, when observed at high levels in these triple-negative breast cancers, that tamoxifen could be successfully used. The goal of this project funded by the Canadian Breast Cancer Foundation – Prairies/NWT Region is to understand what these molecules do in these tumors at the molecular levels, to potentially use them as therapeutic targets in this especially aggressive form of breast cancers.

University of Alberta – Dr. Hasan Uludag

A Systematic Approach to combinational siRNA silencing in drug resistant Breast Cancer Therapy

Chemotherapy is a common treatment of breast cancers. However, despite the favorable initial response, resistance to drugs can develop rapidly. Multiple mechanisms are responsible for resistance and enhanced cell proliferation/survival in malignant cells. There are indications that silencing proteins involved in these mechanisms could be equally effective in sensitive and resistant cells, and combinational silencing of targets could curb tumor growth without chemotherapy.

The objective of this Canadian Breast Cancer Foundation – Prairies/NWT Region funded project is to identify, and simultaneously silence, novel targets against breast cancer. This University of Alberta research team plans to establish drug resistance in breast cancer cell lines and identify targets for effective combinational silencing by a systematic approach. The results will provide a new approach to breast cancer therapy, which will rely on eradicating proteins in the survival network and minimize the ability of tumors to develop resistance. Since these survival networks are absent in normal cells, the proposed therapy is specific to malignant cells with minimal effect on normal cells.

University of Saskatchewan – Dr. Wei Xiao

Target UEV1A for breast cancer

NF-κB activation is frequently observed in breast cancers; however, what causes its activation remains largely unclear. It has been previously reported that Uev1 plays a critical role in NF-κB activation but it remains uncertain whether this finding is relevant to breast cancer. Recently, this University of Saskatchewan team found two different forms of Uev1 and, surprisingly, only the longer form is elevated in breast cancer cells. During experimentation, it was determined that when the longer Uev1 form is overproduced, breast cancer cells become more mobile and tumors grow faster and metastasize, while reducing the Uev1 level in breast cancer cells limited their migration and metastasis. This project funded by the Canadian Breast Cancer Foundation – Prairies/NWT Region will assist in developing an understanding of how Uev1 plays its role in promoting breast cancer and develop reagents specifically targeting the longer form of Uev1 for the diagnosis and treatment of breast cancers.