Biology of the Breast Cell

To understand the origin of breast cancers, more research is needed on the pre-cancerous, causative events in the normal breast. In breast development, cell populations must co-ordinate migration, proliferation, and apoptosis (cell death) over space and time. In cancer progression these same processes become dysregulated, initially at the genetic level, it leads to the physiological changes associated with malignancy. To better mimic breast and tumor architecture, 3-D cell culture models provide a means to explore potential underlying mechanisms and show the structure of the breast and interaction of its different cell types lead to the development of a tumor. An emerging paradigm identifies “stem cells” as the key to the origin of tumors. Stem cell populations reside in body organs to provide the raw material for tissue regeneration, repair, and for the cyclic proliferation responses to hormones and pregnancy in the breast. If this theory proves correct, then only a small fraction (1- 2 percent) of cells in a tumor mass retain stem cell properties, and these “cancer stem cells” must be selectively targeted to achieve an effective eradication of the disease.

Tumor biology, which the CBCRP refers to as pathogenesis, typically involves basic science cell-based studies. In the past, researchers approached tumor biology from the reductionist level (i.e., studying the contributions of individual genes and proteins to the development of disease). However, over the past decade researchers have realized that the underlying mechanistic driving forces of tumor biology operate though complex, concurrent genetic changes in numerous molecular pathways. Still, it remains the metastatic process that presents the greatest hurdle in our efforts to contain and destroy cancer as it too often presents itself at the time of diagnosis. Breast cancer can spread to almost any region of the body, although metastases are most common to the bone, lung and liver. Understanding the gene and physiological regulatory mechanisms for this cancer cell diaspora is crucial for the design of therapeutic strategies. Other important basic science topics represented in CBCRP’s portfolio include: (1) cell proliferation control mechanisms through the estrogen receptor and growth factor receptors (e.g., Her-2), (2) alterations in DNA repair process that permit genetic damage to accumulate in cancer cells, (3) cell cycle changes that permit division under conditions where normal cells would undergo programmed cell death (apoptosis), and (4) novel biomarkers to distinguish pre-cancerous and cancerous cells from normal breast epithelium and their validation as potential new detection and therapy targets.

Two research topics are presented in this section.

Research Conclusions

Alternative pre-mRNA Splicing in Mammary Epithelial Cells
Normal breast development requires cells to turn individual genes on and off at the appropriate times. In many cases, a single gene can make multiple products that may exhibit different functions by splicing in (retaining) or splicing out (removing) an internal part(s) of the gene's coding sequence known as "exons." Exon splicing can be regulated to allow the cell to make predominantly one spliced product at one stage of development, and an alternate spliced product at another stage. This splicing is essential to keep cancer from occurring, yet little is known about how splicing is regulated in normal mammary epithelial cells or how aberrations in this process develop. John G. Conboy, Ph.D., at the Lawrence Berkeley National Laboratory, and colleagues studied a gene called protein 4.1 to assess how this splicing process works in specialized breast epithelial cells. They already knew that this gene makes one version of its protein in one type of epithelial cell, and a different version, containing an extra spliced exon "17B", in another. This research allowed the team to identify three potential regulatory elements that stimulate or inhibit splicing. They are now studying the sequences of exon 17B and its adjacent regions and investigating whether changes in splicing occur in other genes as well. This research on the normal breast could lead to a new understanding of how breast cancer develops and new targets for cancer treatment.

Angiogenesis in Hyperplasia to In Situ Breast Cancers
Virtually all breast cancer begins as ductal carcinoma in situ (DCIS), but not all DCIS will go on to become invasive breast cancer. Min-Ying (Lydia) Su, Ph.D., at the University of California, Irvine, attempted to use magnetic resonance imaging (MRI) to study whether hyperplasia, DCIS, or invasive cancers contain cells that have the ability to develop new blood vessels, a process known as angiogenesis. However, they were unable to find a reliable way to use MRI to differentiate between the different types of cancers and precancers. The team is now trying to develop a computerized mathematical procedure for characterizing, comparing, and analyzing the different structures of hyperplasia, DCIS, and invasive cancers. This work could lead to the development of a computer-aided diagnostic system for breast MRI that could aid in breast cancer diagnoses and treatment. Results from this research were published in four separate articles, the most recent in Technology in Cancer Research and Treatment 2006; 5(4):401-10.

Characterizing Breast Cancer Cells in Blood and Bone Marrow
Small numbers of cancer cells are known to circulate in the blood of many women with newly diagnosed or metastatic breast cancer. Cancer cells can also be found in the blood forming parts of bone in women with newly diagnosed breast cancer. Whether the presence of these circulating tumor cells (CTCs) increases a woman's risk for recurrent disease is unclear. Robert Carlson, M.D., at Stanford University, and colleagues attempted to isolate CTCs from blood and bone marrow samples taken from women with breast cancer so that they could study the biologic characteristics of these cells. They found that neither of the two commercially available methods for isolating tumor cells was able to obtain sufficient numbers of these cells. Dr. Carlson and his team intend to continue to try to identify methods of isolating CTCs from blood and bone marrow. This work could lead to the development of new methods of assessing which tumors are most likely to recur or spread.

Dissection of Signaling Events in the Mammary Gland in Vivo
Changes that occur in the physical and chemical properties of a cell’s environment act as cues that control many aspects of how a cell functions, including migration, proliferation, differentiation, and death. If a problem develops in one of the many different pathways that cooperate and participate in these processes, it could set the stage for the cellular disorders that lead to cancer. Yuehai Ke, Ph.D., at the Burnham Institute for Medical Research, La Jolla, and colleagues, studied a tyrosine phosphatase, called Shp2, and its associate protein Gab2m in the mammary gland in mice. They learned that Shp2 controls activities inside the cell that regulate the ability of the breast to produce milk, and that when mice are missing Shp2 the mammary gland does not develop properly. They also discovered that Gab2 plays a role in controlling breast cancer growth and metastases. These findings could lead to a better understanding of how breast cancer develops and progresses and to the development of new breast cancer treatments.

Does Disregulation of Centrosomes Cause Breast Cancer?
Cell division is a normal part of the cell cycle. During the cell division process the genetic material is duplicated and the old and new copies are segregated to opposite side of the cell. This procedure prepares the cell to split into two daughter cells that each contains one complete copy of the genetic material. Scientists believe that unequal segregation of the genetic material may be an early step in the formation of breast cancer. Kimberly McDermott, Ph.D., at the University of California, San Francisco, explored why some breast cells do not separate the genetic material into two equal parts. She and her colleagues found that, unlike normal cells, these variant breast cells have more than the two centrosomes. (The centrosome orchestrates where, when, and how the old and new copies of genetic material are segregated during cell division.) They discovered that a tumor suppressor protein, called p16, is involved in the process that leads a cell to acquire an abnormal number of centrosomes. And they demonstrated, for the first time, that cells that have more than two centrosomes do not divide the genetic material equally. These findings strongly suggest that a cell’s loss of the tumor suppressor protein p16 and its acquisition of an abnormal numbers of centrosomes are critical factors in the development of breast cancer. This work could lead to the development of new ways to detect and treat precancerous cells, which could stop breast cancer from occurring. Results of this research were published in PLoS Biology 2006; 4(3):e51.

Early Transitions in Breast Cancer
To improve cancer treatment and prevention, a greater understanding is needed of the earliest steps in the transition of normal cells to cancerous ones. Thea Tlsty, Ph.D., at the University of California, San Francisco, and colleagues have identified a rare population of cells, called variant human mammary epithelial cells (vHMEC) that exhibit characteristics similar to those seen in precancerous breast cells. Dr. Tlsty and her team used a powerful new microscope (dual photon confocal microscopy) to study how the vHMEC take on cancer-like characteristics. They found that vHMEC have a nonfunctioning p16 gene, which prevents the telomeres, which sit on the end of the chromosomes, to accurately keep track of how many times a cell has divided. Dr.Tlsty and her colleagues suggested that this may be the genesis of the telomoeric dysfunction that is one of the hallmarks of a cancer cell. The team also determined that nonfunctioning p16 was associated with an increase in the level of a stress activated protein called COX-2, and that increased levels of COX-2 prevent the cell from properly responding to DNA damage. This demonstrates that stress activation precedes the onset of proliferation, and that these two events occur in the premalignancy stage as a cell transitions from normal to cancerous. The team also discovered that cells called cancer-associated fibroblasts (CAF), which are found in the extracellular matrix that surrounds and supports the cells, can stimulate the growth and alter the appearance of premalignant mammary epithelial cells. All of these findings have the potential to lead to new ways of detecting precancerous cells before they have had the opportunity to transition into cancerous ones.

In Vivo Gene Expression Profiling of Developing Mammary Gland
At different stages in a woman’s life, such as during puberty and during pregnancy, normal breast duct cells receive messages that tell them to start developing the breast ductal tree. Only when the ductal tree is fully formed can the breast produce milk. Hosein Kouros-Mehr, B.S., at the University of California, San Francisco, and colleagues, used a technique called DNA microarray profiling to identify the genes that appear to control the development of this ductal structure. They also examined the communication that occurs between the non-ductal cells and the developing ductal tree. The team found that the genes that are involved in the development of the ductal system mirror those that are involved in the development of other branching systems, such as the airways in the lungs. Mr. Kouros-Mehr and others in the lab of Dr. Zena Werb are now studying how these genes affect the form and shape of the breast’s ductal branches. Learning how normal mammary gland cells communicate with their environment to create the ductal structure may shed light on how this communication goes awry in breast cancer cells. This work could lead to a greater understanding of known breast cancer risk factors, such early menarche and late pregnancy, and the development of breast cancer treatments. A number of publications resulted from this research, including Cell 2006; 127(5):1041-55.

Maspin: Breast Cancer Suppression Through Enzyme Inhibition?
A tumor suppressor gene called maspin was first identified in human breast cancer tumors in 1994. However, it’s still not yet fully understood what maspin is, how it acts biochemically, and whether it works inside or outside the cell. Jeffrey Smith, Ph.D., at the Burnham Institute of Medical Research, La Jolla, and colleagues attempted to clarify how maspin works to keep tumors from metastasizing (spreading) by exploring a novel connection between maspin and another protein complex, called the proteasome, that recycles proteins expressed in a cell. Dr. Smith and his team found that cells that express maspin also express a distinct form of proteasome. This suggests that maspin-expressing cells can contain either a "metastatic" proteasome or a "non-metastatic" proteasome. The team went on to find the areas on the maspin gene that give it the ability to slow or stop metastases from occurring and to demonstrate that maspin affects the type of proteasome that develops. This work could lead to an increased understanding of what triggers metastatic disease as well as new treatments that target the metastatic proteasomes. Results from this study were published in the FASEB Journal 2005; 19(9):1123-4.

A Novel Approach to Inactivate the Estrogen Receptor
Nearly two-thirds of postmenopausal women with breast cancer have tumors that are estrogen receptor (ER)-positive. These tumors are fueled by the hormone estrogen. Hormone therapies, like the selective estrogen receptor modulator (SERM) tamoxifen, are used to treat these tumors. But they are not perfect. Because SERMS are anti-estrogenic in the breast but estrogenic in other tissues, they carry an increased risk for uterine cancer and blood clots. Further, over time, many tumors will stop responding to hormone therapy. Alex So, B.A., at the University of California, San Francisco, studied a region of the ER, called the ligand-binding domain (LBD), that keeps the receptor turned off when estrogen is not present. Once estrogen arrives at the receptor, it releases LBD from its duties. Mr. So and his team also explored the role that a nucleosome, called Swi/Snf, which interacts with a number of proteins that have been linked to breast cancer development, plays in transcribing a gene’s DNA sequence into messenger RNA. Mr. So and colleagues are now trying to develop a model of LBD inactivation of ER. They are also continuing to explore the role of Swi/Snf. This work could lead to the new treatments for ER-positive tumors as well as new methods of keeping these tumors from becoming resistant to current treatments.

Prognostic Value of Ras Activation in Breast Cancer
Biomarkers are used in breast cancer to guide the course of treatment. Gerry Boss, M.D., and Anne Wallace, M.D., at the University of California, San Diego, used a patented biochemical assay to study a protein called Ras that transmits growth-promoting signals from the cell's surface to the nucleus. Ras can either be "active" or "inactive." Drs. Boss and Wallace found that Ras was abnormally activated in 100 (40 percent) of the breast cancer tumors they studied. They are following the women whose tumor tissue they tested to determine whether Ras activation is evidence of increased risk of recurrence or metastasis. At 18 months of follow up, no correlation between abnormal Ras activation and the risk of recurrence was seen. However, it is possible that an association will be seen after a longer follow-up period. If this occurs, Ras activation may one day be used to predict whether a tumor is more likely to recur or metastasize. It could also lead to use of newly developed Ras inhibitors for cancer treatment.

Protective Role of Estrogen Receptor Beta in the Mammary Gland
The hormone estrogen has been found to fuel breast cancer growth. The effects of estrogen are mediated by two similar versions of the estrogen receptor. Estrogen receptor alpha (ERα is known to be the major mediator of growth in the breast. Estrogen receptor beta (ERβ) was only recently identified and its function in the normal breast remains unclear. However, studies have found that ERβ is often missing in breast cancer cells, and that introducing ERβ into breast cancer cells can inhibit cell growth by altering the action of (ERα). Leslie Hodges Gallagher, Ph.D., at the University of California, San Francisco, studied the role of ERβ by developing breast cancer cells that express ERβ when a certain regulator is not present. Dr. Gallagher and her team found that when ERβ was expressed these cells grew more slowly during two specific phases of the cell cycle. They also found that ERβ enhanced the effects of tamoxifen, increasing the rate of cell death. To investigate how the presence of ERβ may differentially regulate genes, the team studied two known estrogen-regulated genes, cyclin D1 and Bik. They found that Bik, a mediator of cell death, responded early to tamoxifen when ERβ was expressed. The team is now studying how ERβ and tamoxifen regulate Bik. This work could lead to the development new treatments for preventing or treating breast cancer.

Proteomic Profiling of Adhesive Structures in Breast Cancer
In order for breast cancer cells to spread (metastasize) to other parts of the body, they must first acquire the ability to change the way they interact with both other cells and their immediate environment. Jason A. Bush, Ph.D., at the Burnham Institute for Medical Research, La Jolla, and colleagues in Dr. Kristiina Vuori’s lab used a breast cancer model to study a class of proteins, called integrins, that help establish and regulate the cellular interactions that take place between the cell and its environment. This work led them to define and validate a new biochemical relationship between an integrin and a specific protease that is often found in increased levels in breast cancer cells. Dr. Bush and his co-workers are now confirming their observations by studying actual breast cancer cell lines. This work will increase our understanding of how cancer cells grow and metastasize and has the potential to lead to the development of new breast cancer treatments.

Role of BI-1 Protein in Breast Cancer Apoptosis
Defects in apoptosis, or programmed cell death, play an important role in the initiation and progression of breast cancer. However, relatively little is known about which apoptosis-regulating genes are expressed in breast tumors. Beatrice Bailly-Maitre, Ph.D., at the Burnham Institute for Medical Research, La Jolla, and colleagues in Dr. John Reed’s lab, investigated an anti-apoptotic protein, called BI-1 (Bax Inhibitor-1), that their lab had recently discovered. They also studied the endoplasmic reticulum (ER), which is found inside the cell’s cytoplasm. The ER transports substances within the cell; it also regulates calcium levels inside the cell in response to chemotherapy. The team found that BI-1 appears to be an important regulator of cell death pathways linked to ER stress in the breast. This finding could lead to new ways of making tumors more sensitive to chemotherapy and to new methods of monitoring a tumor’s response to cancer treatments. Results from this research were published in Molecular Cell 2004; 15(3):355-66, the Journal of Clinical Investigation 2005; 115(10):2656-64, and the Proceedings of the National Academy of Sciences of the United States of America 2006; 103(8):2809-14.

Role of Chromatin Regulator in Breast Cell Growth
ACTR/AIB1, a member of the p160/SRC transcriptional coactivator gene family, was recently found to be present at high levels and/or to have multiple copies in over 30 percent of breast tumors. ACTR interacts directly with the estrogen receptor. However, whether elevated levels of ACTR/AIB1 play a causal role in promoting breast cancer development and progression has not been determined. Hongwu Chen, Ph.D., at the University of California, Davis, found that the presence of the ACTR gene makes noncancerous breast epithelial cells live longer while the overexpression of ACTR in ER-positive breast cancer cells enhances cell growth. This suggests that the ACTR/AIB1 gene could play important roles both in normal human breast cell growth and in breast cancer. Dr. Chen’s team found that elevated levels of ACTR can stimulate the proliferation of breast cancer cells, regardless of whether estrogen or the estrogen receptor are present, as well as overcome the growth inhibitory effect of anti-estrogens. They also noted that ACTR interacts with the cell cycle regulatory protein E2F in cancer cells. The finding that ACTR may interact directly with important cell cycle regulators to promote breast cancer cell growth suggests that learning how to disrupt the interaction between ACTR and E2F could represent a new treatment strategy for women whose tumors have high levels of ACTR.

Role of FGF10 in Early Mouse Mammary Gland Development
Significant breast development takes place before birth in humans and mice. Molecules that control the migration of epithelial cells oversee this early breast development. Studies have suggested that a gene encoding a secreted molecule called Fibroblast Growth factor 10 (FGF10) may control the early steps of breast development. Saverio Bellusci, Ph.D., at Children’s Hospital, Los Angeles, studied the role of FGF10 and its potential interaction with another important family of growth factors, called WNTs in the process of epithelial cell migration (WNTs are known to be involved in normal breast development as well as in the process of tumor progression). Dr. Bellusci and his colleagues demonstrated that FGF10 controls the expression of WNTs as breast development occurs in the mouse embryo. It is likely that these pathways also play a critical role in breast development during both the embryonic and post-natal phases. Learning more about cell migration in normal breast development could allow scientists to create new breast cancer treatments that keep breast cancer cells from spreading to other parts of the body. Findings from this research were published in Developmental Dynamics 2004; 229(2)349-56.

Role of IKKa in Mammary Gland Development
The majority of the cells in the female breast, or the mammary gland as it is called in other mammals, are epithelial cells—the cells that form the milk producing duct where most breast cancers begin. Michael Karin, Ph.D., at the University of California, San Diego, and colleagues studied the molecular mechanisms involved in regulating mammary epithelial cell growth during pregnancy, the time at which the mammary gland becomes a milk-producing organ. The team focused its attention on a protein, called NF-κB, that regulates gene expression in both normal cells and in breast cancer. They identified a biochemical pathway involving NF-κB that leads to the division of mammary epithelial cells. And they created a special mouse that would allow them to study this pathway and its involvement in breast cancer. Dr. Karin and his team discovered that when an enzyme called IKKα was inactivated, the mice were less likely to develop breast cancer. The team now intends to investigate whether IKKα plays a different role in a tumor that is HER2-positive than it does in a tumor that is HER2-negative. They are also going to study a related protein called IKKβ. This research could lead to the development of new breast cancer treatments that work by inhibiting IKKα. Findings from this research were published in Cell 2001; 107(6):763-75 and Nature Reviews Cancer 2002; 2(4):301-10.

Statistical Techniques for Breast Biology and Cancer Research
New molecular profiling technologies allow for the rapid and simultaneous measurement of thousands of genes, proteins, and other molecules. The results provide a "fingerprint" of the state of a cell. For researchers, this technology has the potential to be used to assess how networks that regulate cellular growth become defective in breast cancer. For physicians, monitoring tumors before, during and after therapy could provide molecular portraits that could guide cancer treatment. But before this can occur, advanced, statistically sound analytical techniques must be developed and evaluated. I. Saira Mian, Ph.D., at the Lawrence Berkeley National Laboratory, developed a variety of statistical techniques to identify subtle, but significant, patterns present in the data derived from molecular profiling technologies. These techniques have the potential to provide more reliable diagnoses, uncover previously unrecognized categories of cancer, yield new discovery and imaging tools, and explain why some people respond to cancer treatments while others do not. Findings from this research were published in Genome Biology 2004; (5):R18, The Lancet 2003; 362():440, Journal of Biological Chemistry, 278(2003)3882, Molecular and Cellular Biology 2003; 23():8440, Current Opinions in Cell Biology 2003; 15():753, Mechanisms of Aging and Development 2003;124():109, Signal Processing 2003; (83):729, Nucleic Acids Research 2003(31)6392, Eukaryotic Cell 2002(1)967, and Radiation Research 2002(158)568.

Study of the Apoptotic Phenotype as a Hallmark of Malignancy
Molecular and functional imaging is an important component of the developing field of molecular medicine. For doctors, this imaging may one day make it possible to offer women a non-invasive method of characterizing their tumors and assessing their response to treatment. To enhance her understanding of techniques in basic science, Nola Hylton, Ph.D., at the University of California, San Francisco, studied the p53 regulation of the Myc oncogene in genetically engineered mice. This project was performed in the laboratory of her colleague Dr. Gerard Evan at UCSF. This training will help Dr. Hylton to develop better imaging methods for the detection, prognosis, and treatment of breast cancer in women.

Targeting of DNA Methylation in Mammary Epithelial Cells
Many breast cancers have disorders that keep genes that control cell growth from working the way that they should. These abnormalities can be genetic mutations that alter the DNA sequence of a particular gene, or they can be epigenetic alterations that affect the cell without directly altering its DNA. A chemical change to DNA called DNA methylation is one of the best-known epigenetic traits. David Liston, Ph.D., at the Salk Institute, La Jolla, and colleagues explored the molecular mechanisms by which DNA methylation targets two growth control genes called p16 and p15. (p15 is not silenced in breast cancer cells, but it is very similar to p16, which is.) The team investigated the mechanism by which a protein called TGF-beta induces p15, and identified three proteins, called transcription factors, that bind to the p15 gene and may cooperate with TGF-beta. Since the failure to stop growing in response to TGF-beta is a key abnormality in breast cancer cells, this research on how TGF-beta regulates its target genes could provide important clues as to how DNA methylation occurs and how it affects cancer progression.

Targeting Estrogen Receptors to Mouse Mammary Epithelium
The uterus and breasts require estrogen for normal growth. Estrogen also fuels most breast cancers. However, precisely which cells in the normal breast respond to estrogen and become cancerous is not known. Richard Price, M.D, at the University of California, San Francisco, and colleagues studied excess estrogen signals by adding a super-active estrogen receptor to mouse mammary glands. The experimental mice were followed over time and their mammary glands were sampled for growth abnormalities. Numerous abnormalities were found, which suggested that the super-active estrogen receptor was able to stimulate excessive growth. Dr. Price intends to continue to use these mice to conduct more research on the role of excess estrogen signaling in the development and the treatment of breast cancer.

Translational Proteomics of Normal to Benign Breast Disease
How benign breast disease develops is not well understood. Proteins are the functional components of the cell that are directly responsible for disease development. Proteomics—the study of proteins and their functions—has the potential to provide new information about early cellular changes that could lead to better diagnoses of early stages of breast disease. Dave S.B. Hoon, Ph.D., Armando E. Giuliano, M.D., and Lori L. Wilson, M.D., at the John Wayne Cancer Institute, Santa Monica, used ProteinChip array technology to create a proteomic profiling assay that could be used to identify significant proteomic signatures linked with breast disease. The team identified proteins that are present in breast cancer and proteins that could predict which tumors are more likely to have already spread to the lymph nodes. They also developed an algorithm that could be used to identify protein signatures that are linked to breast cancer. The team is now working on further characterizing these specific proteins and on developing detection assays. This work could lead to the development of a proteomic-based tool that could be used to diagnose early breast disease.

Understanding Aging Effects in the Breast
Most human cells are programmed to stop growing and dividing after they have produced a certain number of daughter cells. Cells damaged by radiation and other agents may also stop dividing. This permanent arrest in cell growth is called cellular senescence. Studies have found that senescent cells acquire characteristics that enable them to stimulate the growth of nearby cells. Ana Krtolica, Ph.D., at the Lawrence Berkeley National Laboratory, and colleagues, explored whether the increase in the number of senescent cells that are present in a person’s body as they grow older is linked to the increase in breast cancer risk that occurs with age. The team established how changes in the environment induced by aging and/or tissue damage can work together with mutations that can develop inside a breast cell to promote the transformation of a normal cell into a cancer cell. And they identified some of the factors produced by senescent cells that contribute to the changes they observed. The team is continuing to look for the molecules that may be responsible for the effects of aging or damaged tissue on the breast. This work could lead to the identification of molecules that could be the target of new breast cancer treatments. Findings from this research appeared in the International Journal of Biochemistry and Cell Biology 2002; 34(11):1401-14, Cytometry 2002; 49(2):73-82, Nature Cell Biology 2003; 5(8):741-7, Advances in Gerontology 2003; 11:109-16, EMBO Journal 2003; 22(16):4212-22, Journal of Cell Science 2005; 118(Pt. 3):485-96, and International Journal of Biochemistry and Cell Biology 2005; 37(5):935-41.

Grants in Progress: 2006

A Novel Epithelial-Stromal Model of Metastatic Breast Cancer
Richard Neve
Lawrence Berkeley National Laboratory

A Role for p53 and Splicing Factor SAP145 in Breast Cancer
Lan Truong
University of California, Irvine

Apaf-1 is a Transcriptional Target for the ZNF217 Oncogene
Sheryl Krig
University of California, Davis

Axon Guidance Proteins in Mammary Gland Development
Lindsay Hinck
University of California, Santa Cruz

Breast Cancer Studies in a 3-D Cell Culture System
Robert Abraham
The Burnham Institute of Medical Research

Defining Mammary Cancer Origins in a Mouse Model of DCIS
Alexander Borowski
University of California, Davis

Defining Mutagenesis Pathways in Breast Cancer Evolution
Ewa Lis
The Scripps Research Institute

Discovering Novel Cell-ECM Interactions in Breast Cells
John Muschler
California Pacific Medical Center Research Institute

Epithelial Polarity, Organization and the Angiogenic Switch
Nancy Boudreau
University of California, San Francisco

Evaluating the Role of RIN1 in Breast Cancer
Marc Milstein
University of California, Los Angeles

Functional Analysis of BORIS, A Novel DNA-binding Protein
Paul Yaswen
Lawrence Berkeley National Laboratory

Histone Methylation as a Marker of Breast Cancer Progression
Judd Rice
University of Southern California

Identification of BRCA1 Ubiquitylation Targets
Peter Kaiser
University of California, Irvine

Identifying Metastatic Breast Cells from Peripheral Blood
Kristin Kulp
Lawrence Livermore National Laboratory

Imaging RhoC-induced Breast Cancer Invasion and Angiogenesis
Konstantin Soletov
University of California, San Diego

Integrated Proteomic and Metabolic Analysis of Breast Cancer
Kyle Chiang
The Scripps Research Institute

Modulation of TGF-beta Signaling in Mammary Epithelial Cells
Xiaoman Xu
University of California, Irvine

Normal Mammary Biology of Phosphorylated Prolactin
Ameae Walker
University of California, Riverside

Novel Approach to Analyze Estrogen Action in Breast Cancer
Brian Elicieri
La Jolla Institute for Molecular Medicine

Oxidative Stress and Estrogen Receptor Structural Changes
Christopher Benz and Bradford Gibson
Buck Institute for Age Research

Profiling Enzyme Activities in Human Breast Cancer
Benjamin Cravatt and Stefanie Jeffrey
Scripps Research Institute and Stanford University

Reactivation of the Inactive X Chromosome and Breast Cancer
Angela Anderson
University of California, San Francisco

Regulation of Mammary Epithelial Invasion by MMPs and FGFs
Andrew Ewald
University of California, San Francisco

The Role of Gli3 in Mouse Embryonic Mammary Gland Formation
Jacqueline Veltmaat
Childrens Hospital, Los Angeles

Role of Integrins in Lymphangiogenesis During Breast Cancer
Barbara Susini
University of California, San Diego

Role of Oxidative DNA Damage to Breast Tumor Progression
Paul Henderson
Lawrence Livermore National Laboratory

Role of Telomerase in Mammary Stem Cell Function
Steven Artandi
Stanford University

Stem Cells in Breast Cancer Metastasis
Brunhilde Felding-Habermann, John Yates & Evan Snyder
Scripps Research Institute and The Burnham Institute of Medical Research

Stem Cells of Molecularly Diverse ER Negative Breast Cancers
Stefanie Jeffrey
Stanford University

Structural Analysis of Cancer-Relevant BCRA2 Mutations
Henning Stahlberg
University of California, Davis

Survivin: Target for Breast Cancer Brain Metastases
Florence Hofman
University of Southern California

The Role of B-Myb in Human Breast Cancer Progression
Joseph Lipsick
Stanford University

The Role of LMO4 in Breast Cancer
Zhengquan Yu
University of California, Irvine

The Role of the ECM in Breast Cancer DNA Damage Repair
Albert Davalos
Lawrence Berkeley National Laboratory

Research Initiated in 2006

A Candidate Marker of Mammary Tumor Initiating Cells
Alexey Terskikh
The Burnham Institute of Medical Research

A New Marker for Mammary Epithelial Stem Cells?
Robert Oshima
The Burnham Institute of Medical Research

Analysis of MicroRNA Expression in Breast Cancer Stem Cells
Yohei Shimono
Stanford University

Identification of Metastasis Competent Breast Cancer Cells
Barbara Mueller
La Jolla Institute for Molecular Medicine

Inflammation Alters Transcription by ER in Breast Cancer
Eliot Bourk
University of California, San Diego

Isolation of Cancer Precursors from Normal Human Breasts
Bob Liu
University of California, San Francisco

Modeling, Targeting Acetyl-CoA Metabolism in Breast Cancer
Chen Yang
The Burnham Institute of Medical Research

MYC and CSN5 in the Breast Cancer "Wound Signature" Profile
Adam Adler
Stanford University

Profiling Drug Metabolism (P450) Proteins in Breast Cancer
Aaron Wright
Scripps Research Institute

Role of Cell Division Asymmetry in Breast Cancer Stem Cells
Claudia Petritsch
University of California, San Francisco

The Role Chk1 in Breast Cancer DNA Damage Repair
Jennifer Scorah
Scripps Research Institute

The Role of Estrogen-Related Receptors in Breast Cancer
Anastasia Kralli
Scripps Research Institute

The Role of Podosomes in Breast Cancer Metastasis
Barbara Blouw
The Burnham Institute of Medical Research

The Role of Serine and Metallo-Hydrolases in Breast Cancer
Sherry Niessen
Scripps Research Institute

Twist Activation in Breast Cancer Metastasis
Jing Yang
University of California, San Diego