Detection, Prognosis, and Treatment

Until we learn how to prevent all breast cancers, detection, prognosis, and treatment are research areas that need to be pursued. The detection, prognosis, and treatment topics funded by the CBCRP continue to change as novel technologies and approaches come under investigation. Breast cancer detection technology is moving past traditional mammography; diagnosis is depending on understanding the genetic profile of tumors rather than the anatomy; and treatment is moving toward more tailored and personalized approaches. Alternative therapies and drugs, especially those derived from plants, engender intriguing areas of investigation. Taken together these advances are leading to patient care that treats women appropriately and spares them unnecessary side effects.
Two research topics are represented in this section:

Research Concluded in 2009

Multinuclear MRI of Breast Tumors
Earlier and more accurate diagnosis, as well as better selection and assessment of treatments, could dramatically improve breast cancer survival. Brian Hargreaves, Ph.D., at Stanford University, in Palo Alto, and colleagues investigated whether using simultaneous multinuclear magnetic resonance imaging (MRI) of both protons and sodium would make it easier to accurately diagnose breast tumors. They built two different sets of MRI hardware appropriate for combining sodium MRI with standard proton MRI. Both sets of hardware allow acquisition of sodium and proton MR images without moving the subject. This permits the higher-resolution proton image to be used as an anatomic reference for sodium images, and also allows direct comparison between different imaging techniques. They are now investigating the relationship between levels of sodium MRI and tumor malignancy. This research has the potential to lead to new ways to detect breast tumors as well as advance our understanding of how the environment that surrounds cancer cells contributes to their growth.

Factors Influencing Breast Cancer Screening Among Older Thai
The lower incidence of breast cancer seen in Asian women in the U.S. may be due, in part, to their having a lower rate of participation in mammography screening Mary Jo Clark, Ph.D., R.N., at the University of San Diego, and Bulaporn Natipagon-Shah, Ph.D., R.N, of the Thai Health and Information Service, in Los Angeles, conducted focus groups with Thai women to learn why they do, or do not, get a mammogram. They then used this information to develop a questionnaire for telephone interviews they conducted with 360 Thai women between the ages of 40 and 81 living in Los Angeles, Riverside, Orange, San Bernardino, and San Diego counties. They found that although a majority of the women (84%) had had a mammogram at some time, almost half (44%) did not get a mammogram annually, as is recommended by the American Cancer Society. This was due to a lack of health insurance, the cost of screening, language difficulties, and a lack of time. The investigators intend to use this information to develop an educational intervention that could be used to increase mammography screening in Thai women.

Intraoperative Assessment of Surgical Lumpectomy Margins
Approximately 20 to 30 percent of patients who have a lumpectomy require a second surgery because tumor cells were found at the edges of the tissue (the margin) that was removed during their first surgery. Currently, there is no good way to determine during surgery whether the margin is free of cancer cells. Armando Giuliano, M.D., at the John Wayne Cancer Institute, in Santa Monica, and colleagues developed a probe for assessing these margins during surgery. After they found that the probe did not work well, they developed a second probe and then a camera. None of the techniques was found to be sensitive enough to detect small numbers of cancer cells at the margin. They were, however, able to identify two molecular markers that might be effective in detecting breast cancer cells in breast tissue. They are now studying whether these markers could be used during surgery to determine if the surgical margins are cancer-free.

Modulation of Breast Cancer Stem Cell Response to Radiation
Breast cancer stem cells make up only 1 to 2 percent of the total tumor cell population. However, it may be these cells that are responsible for a cancer recurrence or metastases. Frank Pajonk, M.D., Ph.D., at the University of California, Los Angeles, and colleagues used breast cancer cell lines to investigate how breast cancer stem cells respond to radiation treatments. They successfully verified that these cells were less likely to respond to radiation, and demonstrated that they do not experience as much damage from radiation. Dr. Pajonk and his team also discovered a new breast cancer stem cell marker that can be used to identify, track, and target breast cancer stems cells in vitro and in vivo. In 2009, Dr. Pajonk was awarded two additional years of CBCRP funding to continue this research, which has the potential to identify a way to make breast cancer stem cells more responsive to radiation. Findings from this research were published in the Journal of Cellular Biochemistry 108(2009)339 and the Journal of the National Cancer Institute 101(2009)350.

An Approach to Anti-estrogen Resistance in Breast Cancer
Many patients who start on anti-estrogen treatments, like tamoxifen or the aromatase inhibitors, ultimately develop tumors that are resistant to these drugs. To learn more about why this resistance occurs, Oksana Tyurina, Ph.D., at the University of California, San Diego, and colleagues studied a novel hormonal signaling pathway in which ER, its cofactors and N-CoR transcriptional machinery interact in order to mediate the inhibitory effects of estrogen receptor (ER) responsive genes. They are now conducting studies aimed at identifying the mechanisms of ER regulation on an epigenetic level. Dr. Tyurina intends to continue pursuing this line of research using zebrafish or mouse model systems. This work has the potential to help explain why some tumors do not respond to anti-estrogen treatments or develop resistance to these treatments, and could lead to the development of new anti-estrogen therapies.

Sulforaphane: Its Potential for Treatment of Breast Cancer
Epidemiological data suggests that a diet rich in cruciferous vegetables, such as broccoli, cabbage, and cauliflower, provides better protection against breast cancer than a diet containing other fruits and vegetables. This may be because cruciferous vegetables contain an anticancer compound called sulforaphane (SFN). Olga Azarenko, M.A., at the University of California, Santa Barbara, and colleagues analyzed the anticancer activities of SFN to determine how it kills cancer cells. They discovered that a protein, called tubulin, that makes up the microtubules (the hollow structure inside cells that help them to divide) is one of the SFN’s important cellular targets. The chemotherapy drug paclitaxel works by binding to the microtubules in cancer cells, and the research team conducted additional laboratory studies that showed that combining SFN with paclitaxel enhanced its effectiveness. Ms. Azarenko intends to continue to study how SFN affects human breast cancer cells. This work has the potential to lead to new methods of treating breast cancer or reducing breast cancer risk. Findings from this research appeared in Carcinogenesis 29(2008)2360.

Determinants of Response to Microtubule Stabilizing Drugs
The taxane compounds paclitaxel (Taxol) and docetaxel (Taxotere) are important components of breast cancer chemotherapy regimens. These drugs work by binding to microtubules (the hollow structures inside cells that help them to divide). However, tumors may not respond to or can eventually become resistant to these drugs. Tatana Spicakova, Ph.D., at Stanford University, in Palo Alto, and colleagues used breast cancer cell lines to investigate whether mutations in or altered expression levels of two microtubule-associated proteins, MAP-Tau and MAP4, contributed to taxane resistance by altering the drugs' ability to successfully target the microtubules. They found that Tau levels may be associated with taxane response, that taxane-resistant cell lines express substantially higher levels of MAP-Tau compared to the parental cell line, and that knocking down Tau activity did not result in increased sensitivity to paclitaxel. Their work could lead to the development of a way to predict which tumors are not likely to respond to taxane therapy.

Topoisomerase-IIa as a Predictor of Anthracycline Response
About 25 percent of women diagnosed with breast cancer have tumors that have extra copies of a gene called HER2. These tumors are referred to as HER2-positive. The HER2 gene is located close to a second gene known as TOP2A. About 30 to 40 percent of women with HER2-positive tumors also have tumors that have extra copies of the TOP2A gene. HER2-positive tumors have been shown to respond to anthracycline chemotherapy drugs. However, it may be a tumor’s TOP2A status that actually predicts whether it will respond to an anthracycline. Michael Press, M.D., Ph.D., at the University of Southern California, in Los Angeles, is using tumor tissue from women enrolled in the Breast Cancer International Research Group-006 clinical trial, which is evaluating three different treatment regimens in women with HER2-positive tumors, to assess whether a relationship exists between the amount of TOP2A protein and various levels of TOP2A gene amplification. These findings could lead to new ways of determining which tumors are most likely to respond to an anthracycline. Dr. Press was awarded a IDEA renewal grant to continue this investigation.

Novel Cytokine Immunotherapy for Breast Cancer
Conventional chemotherapy drugs are usually accompanied by severe side effects because they kill normal cells along with cancer cells. Immunotherapy is new type of treatment that, like a vaccine, harnesses the body’s natural defenses to recognize and kill cancer cells. Amanda Goldrath, Ph.D., at the University of California, San Diego, and colleagues used a new mouse breast cancer model both to determine whether a new immune-stimulatory agent called IL-15 complexes could reduce tumor size and to characterize the type of immune response it initiates. Their studies demonstrated, for the first time, that an IL-15 cytokine complex could stop tumor growth in a mouse model that typically does not respond to immunotherapy. These findings could lead to the development of an immunotherapy agent that could be used to treat breast cancer. Findings from this research appeared in Blood 112(2008)3704.

Exploring the Role of PARP Inhibitors in Breast Cancer
About 5 to 10 percent of breast cancer cases occur in women with a BRCA1 or BRAC2 genetic mutation. PARP is an enzyme that is needed to repair DNA that has become damaged. A new class of drugs called PARP inhibitors selectively kills breast cancer cells that have a BRCA1 or BRCA2 genetic mutation, and are currently being studied in clinical trials. Karlene Cimprich, Ph.D., at Stanford University, in Palo Alto, and colleagues developed a method of detecting genes the might be needed to keep cells alive when PARP inhibitors are present. To date, their assay has identified three genes that may predict sensitivity to PARP inhibitors. Dr. Cimprich and her team are now working with their collaborator to determine if these are mutated in breast cancer cells known to respond to PARP inhibitors. This work could lead to the identification of other types of tumors that may be responsive to PARP inhibitors.

Nur77-derived Peptides as a Novel Breast Cancer Therapy
The protein BcI-2, which plays a role in cell death, is often elevated in breast cancer cells. As a result, it helps to keep these cells alive as well as protect them from cancer drugs and radiation therapy. Xiao-Kun Zhang, Ph.D., at The Burnham Institute for Medical Research, in La Jolla, and colleagues recently discovered that another protein, called Nur77, could be stimulated to convert Bcl-2 from a protector to a killer of cancer cells. Proteins are typically too big to get past cell membranes, which makes them unsuitable for use as drugs. Dr. Zhang and his team tried to identify the active region of the Nur77 protein so that they could mimic it with smaller protein fragments or peptides. They were able to identify a peptide that could convert Bcl-2 from a protector to a killer of breast cancer cells, in a similar manner as the parent protein, Nur77, and their studies showed that this peptide was not only active against breast cancer tumors grown in animals, but left normal cells unaffected. They also identified an enantiomer (a structural mirror image) of this peptide that is more stable and active than the original peptide. These findings raise the possibility that small molecule Bcl-2 converters could eventually be used as a new breast cancer treatment. Findings from this research were published in Expert Opinion on Therapeutic Targets 11(2007)69; Oncogene 25(2006)4725;  Free Radical Biology and Medicine 44(2008)1334; Cancer Cell 14(2008)285; and Cancer Research 68(2008) 8871.

Research Initiated in 2009

6th Symposium on the Intraductal Approach to Breast Cancer
Dixie Mills
Dr. Susan Love Research Foundation

Antibody-based Targeting of Breast Cancer Stem Cells
Claudia Gottstein
University of California, Santa Barbara

Chemerin as an Immunotherapeutic Agent in Breast Cancer
Russell Pachynski
Palo Alto Institute for Research & Education

Combating Breast Cancer with the Wellderly Immune Repertoire
Brunhilde Felding-Habermann
Scripps Research Institute

Compounds Blocking Assembly of LRH-1 in Breast Cancer
Cindy Benod
University of California, San Francisco

Diffusion-weighted MRI in Monitoring Breast Cancer Treatment
Lisa Singer
University of California, San Francisco

Inhibitors of Condensin I as Chemotherapy for Breast Cancer
Kyoko Yokomori
University of California, Irvine

Membrane-associated Estrogen Receptors in Breast Cancer
Richard Pietras
University of California, Los Angeles

Metabolite Imaging to Identify Drug Resistant Breast Cancer
Trent Northen
Lawrence Berkeley National Laboratory

Modulation of Breast Cancer Stem Cell Response to Radiation
Frank Pajonk
University of California, Los Angeles

A Predictive Factor for Eribulin Treatment of Breast Cancer
Jennifer Smith
University of California, San Francisco

Reducing Surgical Morbidity of Breast Cancer Staging
Steven Chen
University of California, Davis

Sound Speed Tomography for Early Breast Cancer Detection
Jakob Nebeker
University of California, San Diego

Survival in de novo and Recurrent Metastatic Breast Cancer
Sumanta Pal
Beckman Research Institute of the City of Hope

Targeting DNA Repair Function of Breast Cancer Stem Cells
Xiaohua Wu
Scripps Research Institute

Research in Progress

Breast Cancer Treatment Monitoring Combining MRI and Optics
Catherine Klifa
University of California, San Francisco

Chemical Inhibitors of Hsp70 for Breast Cancer
Chung-Wai Shiau
The Burnham Institute of Medical Research

Differential Optical Mammography
Gregory Faris and Christopher Comstock
SRI International and University of California, San Diego

Engineering EGFR Antagonists for Breast Tumor Targeting
Jennifer Lahti
Stanford University

ID4: A Prognostic Factor of Breast Cancer Metastasis
Dave Hoon
John Wayne Cancer Institute

Inhibition of Brain Metastases in Breast Cancer
Brunhilde Felding-Habermann
Scripps Research Institute

Intraductal Therapy of DCIS: a Presurgery Study
Susan Love
Dr. Susan Love Research Foundation

Mechanisms of HSP90 Inhibitor Action in Breast Cancer
Cynthie Wong
Beckman Research Institute of the City of Hope

Molecular Imaging of Breast Cancer Using Breast PET/CT
John Boone
University of California, Davis

Molecular Imaging of Metastatic Lymph Nodes in Breast Cancer
Ella Jones
University of California, San Francisco

Neural Stem Cell Therapy for Breast Cancer Brain Metastases
Brunhilde Felding-Habermann
Scripps Research Institute

Polyamide HIF Inhibitors to Block Breast Cancer Metastasis
John Phillips
California Institute of Technology

Real-time 3D Ultrasound Image-guidance for Breast Surgery
Michael Bax
Stanford University

Development of a Breast MRI Computer-Aided Diagnosis System
Ke Nie
University of California, Irvine

Functional Breast MRI with BOLD Contrast
Rebecca Rakow-Penner
Stanford University

Genetics of Tamoxifen Response
Elad Ziv
University of California, San Francisco

Imaging of Novel Stem Cell Therapy Targeting Breast Cancer
Joseph Wu, M.D.
Stanford University

Inhibition of TF Signaling as Novel Breast Cancer Therapy
Wolfram Ruf
The Scripps Research Institute

Nanotherapy for Breast Cancer Targeting Tumor Macrophages
Gaurav Sarma
The Burnham Institute for Medical Research

Novel Anti-HER2 Fragments for Better Detection and Therapy
Shannon Sirk
University of California, Los Angeles

Novel Small Proteins for PET Imaging of Breast Cancer
Zhen Cheng
Stanford University

Stratifying DCIS Biopsies for Risk of Future Tumor Formation
Thea Tlsty
University of California, San Francisco

Topoisomerase-IIa as a Predictor of Anthracycline Response
Michael Press
University of Southern California

Treating BC Brain Metastasis with Cytotoxic Lymphocytes
Barbara Mueller
Sidney Kimmel Cancer Center