Grants/Breast Cancer Research Program
LSCRF awards seed funding for research that demonstrates the potential to improve the detection and treatment of breast cancer. These grants help researchers pursue promising ideas and novel concepts. For projects that demonstrate great potential, researchers can then pursue larger grants from organizations and governmental agencies such as the National Cancer Institute. The breast cancer leadership at Northwestern annually selects the most worthy projects. Funding to explore new ideas is essential to finding a cure for breast cancer.
2011 Grant Listing
Effect of CDK Inhibition on Smad3 and Cyclin Overexpressing Breast Cancer Cells in vitro and in Primary and Metastatic Xenografts in Mice
Principal Investigator: Jacqueline S. Jeruss, MD, PhD
The goal of this research is to further understand the mechanism by which Smad3, a member of the TGF-beta superfamily of growth regulatory proteins, acts to inhibit breast cancer growth and development. Certain aggressive breast cancer sub-types have high amounts of proteins called cyclins, such as the basal breast cancer subtype or BRCA mutation-associated malignancy. We hypothesize that cyclins act to inhibit normal function of Smad3, promoting breast cancer growth and metastasis. To study inhibitory effects of cyclin activity on Smad3 action, experiments will investigate Smad3 activity in normal breast cells, cancer cells that have a more gentle biology and cancer cells with high cyclin activity. Our work will focus on the use of treatments called CDK inhibitors, as well as standard chemotherapy, to restore Smad3 activity in cell proliferation assays, 3-dimensional tumor models, and mice with either primary or metastatic breast tumors. Through these studies we expect to show that cancers with high cyclin levels, treated with CDK inhibitors and chemotherapy, will result in smaller primary tumors, delayed metastatic spread and longer time to metastatic disease progression, when compared to tumors treated with chemotherapy alone. This work should thereby contribute to the ongoing pursuit of a breast cancer cure.
Topical pharmacotherapy for breast cancer prevention: pharmacokinetics and distribution of topically applied drugs
Principal Investigator: Seema A. Khan, M.D.
Many women at high risk for breast cancer decline to take medicines that are proven to prevent breast cancer because these cause unwanted (and sometimes dangerous) side effects. However, for breast cancer prevention we only need good concentrations of medication in the breast; the amount that appears in the circulation causes collateral damage. We hypothesize that because the embryological origins of the breast are in the skin (it is a modified sweat gland), breast cancer prevention drugs can be given through the skin of the breast and will be concentrated in the breast, but circulating levels will be low, so that side-effects are unlikely. The study we are proposing will test this idea: women needing mastectomy will be asked to wear a patch of the pain drug fentanyl for 36 hours, either on the skin of the breast to be operated, or on the skin of the belly. In both groups, we will measure the drug concentration at the time of surgery, in the blood and in the breast tissue. We expect that women who wear the patch on the breast will have significantly higher concentrations in the breast than women who wear it on the belly. The results of this study will provide important and needed confirmation of the idea that transdermal medications will concentrate in the breast, and will allow us to pursue parallel studies for development of these medications.
The role of syndecan 2 in breast cancer metastasis to the brain
Principal Investigator: Jennifer E. Koblinski, PhD
Approximately 10-20% of breast cancer patients have brain metastases. Brain metastases are viewed as a late complication of breast cancer for which few effective treatment options exist. Therefore, resolving the mechanisms of metastasis to the brain is clinically important. Syndecan (Sdc) are a family of four proteoglycan receptors that have been found to be key regulators in many different types of cancer. Sdc-1 expression has been reported to be a negative predictor of disease free survival and overall survival of breast cancer patients and expression of both Sdc-1 and -4 is associated with increased growth rate in breast tumors; however, little is known about the effect of Sdc2 expression in breast cancer growth and metastasis. A direct connection between these receptors and brain metastasis has not yet been shown. We have found that Sdc2 expression is important for breast cancer metastasis to the brain in an in vivo model system. This proposal will test the central hypothesis that Sdc2 is expressed in breast cancer brain metastases and the primary tumor, and that Sdc2 expression will be a marker for breast cancer metastasis to the brain. This may lead to development of new biomarkers for breast cancer metastasis.
Sprouty in breast development and EGF/Neu Signaling
Principal Investigator: Jonathan D. Licht, MD
Breast cancer arises from a number of genetic alterations including the activation of signaling molecules that stimulate cell growth and the loss of inhibitors of cell growth. The HER2 gene, encoding a signaling receptor, is highly expressed in about 1/3 of breast cancer cases. The Sprouty genes are inhibitors of signaling, silenced in the great majority of breast cancer. Hence, amplification of HER2 and loss of Sprouty function is a common situation in breast cancer. We believe that loss of Spry plays a causal role in breast cancer and will model this hypothesis in mice. Such mice may represent a more accurate model of human breast cancer. In addition we will study the biochemical mechanism by which Spry inhibits HER2 with the aim of discovering new therapeutic approaches to breast cancer.
Effect of percutaneous 4-OHT on mammographic breast density and MRI enhancement in patients with newly diagnosed DCIS
Principal Investigator: Lilian Wang, MD
Tamoxifen, an anti-estrogen, has been shown to decrease both mammographic breast density (BD) as well as MRI background parenchymal enhancement (BPE). Its active metabolite, 4-OHT, when applied topically to the breast, has the potential for similar results while avoiding some of the systemic toxicities of oral tamoxifen. This study is being performed to compare the effects of topical 4-OHT and oral tamoxifen on BD and BPE in patients with ER+ DCIS. Changes in MR enhancement of DCIS after treatment will also be evaluated, using the proliferation factor Ki-67 as the gold standard. Patients will be randomized to 6 weeks of treatment with either topical 4-OHT and oral placebo or topical placebo and oral tamoxifen. BD and BPE pre- and post-treatment will be compared. Extent of enhancement and enhancement kinetics of DCIS will be evaluated on pre- and post-treatment MRIs. We hypothesize that 4-OHT will decrease BD and BPE to a similar degree as oral tamoxifen. MRI enhancement of DCIS is expected to decrease after therapy. Changes in BD and BPE may be helpful intermediate markers of efficacy of 4-OHT in breast cancer treatment or prevention settings. MR may be the most sensitive modality for detecting biologic response of DCIS to endocrine therapy.
2010 Grant Listing
Aromatase: A Molecular Link for Obesity-induced Breast Cancer Risk
Principal Investigator: Dong Chen, PhD
Obesity increases breast cancer risk by 50% among postmenopausal women. The molecular links for obesity-induced breast cancer predisposition, however, remain unknown. Aromatase is a key enzyme for estrogen biosynthesis. Abnormally high expression of aromatase in breast adipose tissue promotes breast cancer pathogenesis and progression. Because obesity increases the mass of adipose tissue where aromatase expression occurs, and increases the production of adipokines (e.g. TNFa and PGE2) and the activity of molecular pathways (e.g. the JNK pathway) that stimulate aromatase expression in cultured primary human breast adipose fibroblasts, we hypothesize that obesity leads to abnormally high expression of aromatase in breast adipose tissue, resulting in elevated levels of estrogen in the breast and predisposition to breast cancer. At the molecular level, we propose that obesity triggers production and release of adipokines that induce aromatase expression in a c-Jun N-terminal kinase 1 (JNK1) dependent manner in breast adipose tissue. We will test this hypothesis by using postmenopausal obese mouse models.
Mammary Development and Tumorigenisis in CypA and CypB Knockout Mice
Principal Investigator: Charles V. Clevenger, MD, PhD
The hormone prolactin contributes to the development and progression (i.e. metastasis) of human breast cancer. Research from our lab has shown that the actions of prolactin in normal and malignant breast tissues are mediated by two prolyl isomerase proteins named cyclophilin A and cyclophilin B (CypA/B). To better understand the function of these proteins during normal and malignant breast development, our lab has generated genetic variants of mice lacking either CypA or B (i.e. “knockout” mice). Preliminary analysis of these mice demonstrates defective mammary development, confirming significant roles for these proteins in the mammary gland. It is the goal of this project, therefore: 1) to complete the characterization of these knockout mice during mammary development, pregnancy, and lactation, and 2) to determine the effect on the development and progression of mammary tumors when the CypA or CypB knockout mice are crossed with mice genetically predisposed to develop mammary cancer. These studies will enable a precise mapping of the in organism function of CypA and CypB during normal and malignant mammary development and progression.
Targeting Survivin in Triple Negative Breast Cancer
Principal Investigator: Vincent Cryns, MD
Breast tumors which lack expression of the estrogen receptor, progesterone receptor and HER2 (“triple negative” breast cancer) are clinically aggressive, often spreading (“metastasizing”) rapidly to the lungs and brain despite treatment. These tumors do not respond to anti-estrogens or Herceptin because they are estrogen receptor-negative and HER2-negative, the respective targets for these agents. Indeed, the lack of molecular targets in triple negative breast cancer is a major obstacle hindering efforts to develop more effective treatments for these poor prognosis tumors.
Survivin is a protein that is expressed in triple negative breast cancer cells, but not in non-cancerous cells, and functions to prevent cancer cells from dying by a process called “apoptosis”. We hypothesize that by turning off the survivin gene in triple negative breast cancer cells we will make them more sensitive to killing by cancer therapeutics and make them less likely to metastasize to other organs. We will test this hypothesis using gene silencing to turn off survivin expression in triple negative breast cancer cells and then test their sensitivity to chemotherapy drugs and their ability to metastasize in mouse models of breast cancer. In this way, our goal is to identify new drug targets and treatment approaches for poor prognosis triple negative breast cancer.
Effect of Weight Loss on Breast Density Using both Digital Mammography and Breast MRI
Principal Investigator: Nora Hansen, MD
The radiographic appearance of the breast varies according to differences in the relative
distributions of fat and fibroglandular tissue and determines breast density. Breast density is one of the strongest known risk factors for breast cancer. Mammograms are the gold standard radiographic tool to identify breast cancer at an early stage but the ability to identify abnormalities may be obscured by the denseness of a woman’s breast tissue. Breast MRI has been shown to be helpful in identifying abnormalities in patients with dense breasts and may be a more accurate way to measure breast density since it is a volumetric measure rather than a two-dimensional measurement. Obesity is on the rise in the United States at an alarming rate and is a national health concern. Obese patients have less dense breasts yet they have a higher rate of breast cancer. Currently, surgery offers the best chance to lose a significant amount of weight rapidly, maintain the weight loss and improve quality of life. We are proposing to evaluate breast density using mammograms and the more sophisticated breast MRI in obese patients undergoing
gastric bypass surgery to determine if weight loss will have an impact on breast density.
Use of p38MAPK and CHK1 inhibitors to chemo-sensitive p53-deficient breast cancer
Principal Investigator: Hiroaki Kiyokawa, MD, PhD
Cancer resistance to chemo- and radiation-therapies depends on “checkpoints”, i.e., the ability of cells to halt the cell division cycle upon DNA damage. While checkpoint dysfunction is involved in cancer development, the checkpoints also protect cancer cells from chemotherapy or irradiation. Approximately 30% of breast cancers have mutations of the TP53 gene, which is a critical checkpoint component and tumor suppressor. Cancers with TP53 mutations are clinically aggressive and better therapies are needed against them. Importantly, cancer cells with TP53 mutations still undergo cell cycle arrest upon DNA damage, depending on alternative checkpoint pathways mediated by CHK1 kinase. Thus, CHK1 inhibitors have been tested in clinical trials to sensitize p53-deficient cancers to chemotherapies; however, the effectiveness needs improvement. Recent studies suggested that there is another checkpoint pathway mediated by p38MAPK, in parallel to the CHK1 and p53 pathways. The proposed study will examine whether inhibitors of p38MAPK can enhance the action of CHK1 inhibitors to sensitize p53- deficient breast cancer cells to chemotherapeutic drugs such as Gemcitabine and Irinotecan. p38MAPK inhibitors have been used to treat inflammatory diseases and clinically well tolerated.
This study is expected to provide a preclinical foundation for a novel therapeutic strategy against aggressive breast cancers.
Modeling Breast Cancer Metastasis to the Brain
Principal Investigator: Jennifer Koblinski, PhD
Approximately 10-20% of breast cancer patients have brain metastases. Brain metastases are viewed as a late complication of breast cancer for which few effective treatment options exist. Therefore, resolving the mechanisms of metastasis to the brain is clinically important. Currently, there are a limited number of model systems to study breast cancer metastasis to the brain. In order to dissect the mechanisms of metastasis to the brain we must have appropriate models. Our laboratory proposes to develop clinically relevant models for studying breast cancer metastasis to the brain. With this development, the expression of the proteoglycan receptors syndecan (SD)-1 and -4 will be examined in this metastatic process. SD-1 expression has been reported to be a negative predictor of disease free survival and overall survival of breast cancer patients and expression of both SD-1 and -4 is associated with increased growth rate in breast
tumors. A direct connection between these receptors and brain metastasis has not yet been
shown. This proposal will test the central hypothesis that SD-1 and/or -4 are expressed in breast cancer brain metastases and the primary tumor, and that these genes will be markers for breast cancer metastasis to the brain. This may lead to development of new biomarkers for breast cancer metastasis.
Adenosine Analogs: Novel therapeutics for breast cancer
Principal Investigator: Steven Rosen, MD
Early stage breast cancer often recurs in a more aggressive state that is resistant to current therapeutic approaches. Therefore new therapeutic approaches need to be developed for this often fatal disease. We have identified a novel class of adenosine analogs which inhibit RNA synthesis, and consequently inhibit many critical cellular functions. One of these compounds, 8- chloro-adenosine has recently entered phase 1 clinical trial for blood cancers. A second compound, 8-amino-adenosine (8-NH2-Ado) is more potent and holds great promise as a cancer therapeutic. 8-NH2-Ado has unique multi-faceted actions that allows for enhanced cytotoxicity in malignant cell populations in comparison to normal cells. These characteristics make these compounds ideal candidates for treatment of drug resistant breast cancer. We have preliminary data that these compounds are toxic to breast cancer cell lines and here we propose to do further pre-clinical studies of these drugs in tissue culture cells lines and in breast cancer tumor models in mice to determine their clinical potential for the treatment of breast cancer.
2009 Grant Listing
Physical Activity, Sedentary Time and Mammographic Breast Density to improve early detection
A healthy level of physical may reduce the risk of breast cancer; however, the role that physical activity plays in reducing breast density is unclear. Further, initial research suggests that sedentary time may also be an important lifestyle risk factor associated with breast density. This study, which measures both physical activity and sedentary time, investigates the relationship of cardiovascular fitness with breast density.
Targeting Cell Surface Death Receptors to Eradicate Breast Cancer Stem Cells
Principal Emerging evidence strongly suggests that breast cancer arises from the genetic alterations in long-lived, self-renewing stem cells. These cancer stem cells are resistant to chemotherapy and likely play a key role in tumor recurrence and metastasis, which is the leading cause of death in breast cancer patients. Accordingly, eradication of cancer stem cells is likely to be essential for eventually curing cancer. In this study, researchers are examining the hypothesis that antibodies known as TRAIL receptors, in conjunction with chemotherapy, provide a therapy that is more likely to eliminate breast cancer stem cells.
The role of obesity and related cellular pathways in breast cancer risk
Adiponectin, a protein secreted by fatty tissue in the body, has been shown to be important in helping to regulate insulin levels. Several studies have demonstrated that women with higher adiponectin levels had a 65 percent reduced risk for breast cancer. This family-based association project will study the role of adiponectin to address questions of considerable medical interest regarding the development of breast cancer.
Local therapy of non-invasive breast cancer using nano-particle bound tamoxifen metabolites
The drug tamoxifen is an effective treatment for estrogen receptor-positive breast cancer because it reduces the risk of local recurrence and prevents new primary tumors of the breast. A system for administering this medication directly at the site of the cancer would be ideal in order to limit systemic exposure and the ensuing side effects such as hot flashes. This study tests the effectiveness of administering tamoxifen in the breast itself using nano-particles as carriers of the drug. Researchers are interested in the ability of these particles to enter cells, be retained by cells and to slowly release the bound drug.
Using mouse models of breast cancer to study the relationship between genetic risks and hormonal pathways
The hormone estrogen plays a key role in breast cancer, and aromatase is the key enzyme that catalyzes the final step in estrogen biosynthesis. Aromatase inhibitors have proven to be effective in eliminating total body estrogen production and are widely used in clinical therapy of breast cancer. Although laboratory research has provided valuable information regarding the relationship between estrogen and breast cancer, very little is known about how locally produced estrogen in breast tissue influences the progress of the cancer. This project will investigate the mechanisms responsible for the initiation, promotion and progression of cancer in laboratory animals.
Dominick's Lynn Sage Scholars
Dominick’s, a leading supermarket chain, has partnered with Northwestern Memorial Hospital in the quest to develop new methods of diagnosing and treating breast cancer. Through a generous gift from Dominick’s, the hospital is recruiting physician-scientists with expertise in the field of breast cancer research. Funds from this gift will be utilized to set up additional research laboratories to accommodate these new physicians and their teams.
2008 Grant Listing
Targeting CD44 to Eradicate Breast Cancer Stem Cells
Principal Investigator: Vincent L. Cryns MD
Recent evidence suggests that breast cancer arises from the accumulation of genetic alterations in stem cells. CD44 is a stem cell marker, and research shows that when CD44 is present in breast tumor stem cells, the rate at which tumor growth is induced becomes more aggressive. This suggests that breast cancer stem cells are what initiate breast cancer tumors.
Furthermore, these cancer stem cells are resistant to chemotherapy and likely play a key role in tumor recurrence and metastasis. Accordingly, eradication of breast cancer stem cells is likely to be essential for “curing” cancer.
Therefore, Dr. Cryns’ research will focus on the hypothesis that breast cancer stem cells, which are CD44 positive, will be eradicated by activating CD44 antibodies. Dr. Cryns predicts that this CD44 antibody-therapy will inhibit breast tumor growth, and possibly lead to an entirely new treatment strategy for breast cancer patients.
Mammographic Breast Density Assessment for Breast Cancer Prevention
Principal Investigator: Susan M. Gapstur, PhD, MPH
On a mammogram, fat appears dark whereas other breast tissue that is more dense appears light. The percent of total breast area that is dense, or light, represents what is referred to as mammographic density (density). Multiple recent research studies have demonstrated that women with higher density are at an increased risk for breast cancer compared with women who have lower density. It is possible that higher density levels may mask the appearance of breast cancer on a standard mammogram.
At this time, there is little data that focuses on the association of modifiable lifestyle factors with density and breast cancer. One of Dr. Gapstur’s long term goals is to asses the effects of changes in lifestyle, including nutrition, physical activity, and obesity, with changes in breast density. Dr. Gapstur believes that this research could be particularly useful in developing interventions targeting women who are at high-risk of breast cancer based on the extent of their density.
Therefore, Dr. Gapstur will conduct a pilot study wherein she will assess mammographic density in women participating in a randomized trial of Vitamin D supplementation, in collaboration with investigators at Dartmouth University. She will also collaborate with Dr. Khan at Northwestern Memorial, to conduct mammographic breast density assessments on a large NCI-funded study of women participating in a study of nipple fluid hormone levels.
Decoding the Signatures of Breast Cancer Metastasis
Principal Investigator: Virginia Kaklamani, MD
Principal Investigator: Ming Zhang, PhD
Breast cancer has extremely high morbidity with bone metastasis. Clinical studies by Dr. Zhang and others show that about 70 percent of cancer patients have bone tumors. Since certain breast cancer cells are prone to metastasize to the bone, they must possess some unique features that make the cancer migration possible. These unique features in tumor cells are likely represented by gene expression patterns, which serve as the molecular signatures of bone metastasis.
Dr. Zhang is working to isolate these tumor cells from bone metastasis to determine the gene expression signature for these tumor cells. He hopes that by isolating bone tumor cells that it may be possible to identify the molecular markers for bone metastasis through comparing gene expression patterns between various tumor cells.
Dr. Zhang has identified a list of 86 possible genes that could play a role in breast cancer metastasis to the bone. A gene component called signal transducer and activator of transcription 1 (STAT1) was consistently present in many of the genes on Dr. Zhang’s list. He therefore hypothesizes that STAT1 may act as a master switch, controlling many signal pathways involved in tumor-bone interactions and in breast cancer metastasis. The objective of this research is to study the function of these genes in tumor-bone interaction during the process of bone metastasis.
Roles and Initial Characterization of a Novel Human Protein, THAP7, in Breast Cancer
Principal Investigator: Debabrata Chakravarti, PhD
To understand breast cancer, it is important to study the disease at the molecular level. Dr. Chakravarti has previously isolated a novel family of proteins termed the THAP (Thanatos (death) associated protein) family. His current research focuses on one member of this family; THAP7, which he believes may play a role in breast cancer cell growth and metastasis. Therefore, he is testing the hypothesis that THAP7 is a biomarker for breast cancer, and that THAP7 plays a role in breast cancer progression.
To determine whether there is any correlation between THAP7 and breast cancer advancement, Dr. Chakravarti will perform a series of tissue culture studies, culminating in an examination of THAP7 in breast cancer tissue samples obtained from the Breast Cancer Tissue Repository of the Robert H. Lurie Comprehensive Cancer Center.
If Dr. Chakravarti discovers that THAP7 does in fact play a role in breast cancer cell growth and metastasis, he plans to test anti-THAP7 inhibitors as a future therapeutic intervention.
Function of SIRPa in Breast Cancer
Principal Investigator: Charles V. Clevenger, MD, PhD
Nationwide research has shown that the hormone prolactin (PRL) plays a significant role in the development of breast cancer. Women with elevated levels of PRL are at a notably increased risk of developing breast cancer. The interaction of PRL with other hormones further stimulates the growth of breast cancer.
Recent studies have shown that the protein SIRPa is a protein that facilitates the communication of PRL with other breast cancer relevant hormones. By acting as an intermediary between hormones SIRPa facilitates breast cancer growth and is a likely future target for new anti-breast cancer drugs.
In his proposal, Dr. Clevenger’s research will focus on the relationship between the hormone PRL and the protein SIRPa. He will be working to identify how the actions of SIRPa influence the effects of PRL on breast cancer growth, survival, and spread.
The Molecular Basis of Smad 3 Inhibition in Breast Cancer
Principal Investigator: Jacqueline S. Jeruss, MD, PhD
TGF- is a gene that is often present in breast cancer cells, and it communicates with other cells through a protein called Smad 3. Dr. Jeruss’ previous research has shown that TGF- and its signaling component, Smad 3, play a role in the onset and progression of breast cancer.
At this time, Dr. Jeruss and other researchers are beginning to explore the possibility that Smad 3 may act as a tumor suppressor. If this is the case, then Smad 3 will play an integral role in stabilizing TGF- and halting breast cancer cell growth. Therefore, Dr. Jeruss’ research will focus on the hypothesis that Smad 3 is in fact a tumor suppressor, and that inhibiting Smad 3 could lead to breast cancer progression.
In addition, further clarification of the role of Smad 3 signaling in breast cancer may prove the protein to be a valuable clinical marker of cancer prognosis. A clear understanding of the mechanisms underlying Smad 3 cell signaling is critical to efforts aimed at preventing breast cancer tumor growth.
The Role of Sprouty 1 Gene and Sprouty 2 Gene in HER-2-induced Breast Cancer
Principal Investigator: Jonathan Licht, MD
Proteins in Sprouty genes decrease the signaling pathways between cells, particularly those pathways involving the tumor-promoting effects of the epidermal growth factor family, known for its adverse effects on breast cancer behavior.
Dr. Licht’s previous research has shown that Sprouty genes are silenced, or lost, in up to 90 percent of breast cancer tumors. This means that the Sprouty genes are unable to restrain the cell signaling pathways involved in breast cancer cell growth.
HER-2 is a growth factor receptor, known for its role in breast cancer progression. In the absence of Sprouty genes, HER-2 could have a larger effect on breast cancer growth and development. Dr. Licht’s research hypothesizes that the silencing, or loss, of the Sprouty gene is a cause of breast cancer. Along with his research team, Dr. Licht will be working to identify ways to preserve the tumor-suppressive effects of Sprouty genes.
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