Tag Archives: breast cancer

Key function of mutation in BRCA1 gene discovered

Posted on by
Reply

Richmond, Va. (September 1, 2011) –It is widely known that mutations in the breast cancer susceptibility 1 (BRCA1) gene significantly increase the chance of developing breast and ovarian cancers, but the mechanisms at play are not fully understood. Now, researchers at Virginia Commonwealth University Massey Cancer Center have shown that certain BRCA1 mutations result in excessive, uncontrolled DNA repair, which challenges the prior assumption that mutations in BRCA1 only contribute to breast cancer through a reduction in function.

Recently published in the journal Aging, the study led by Kristoffer Valerie, Ph.D., discovered that certain BRCA1 mutations affecting the BRCA1 C-terminal (BRCT) binding site resulted in excessive DNA repair, or hyper-recombination, which may contribute to the development of breast and ovarian cancers. The BRCT domain is a protein binding site typically found on DNA repair proteins like BRCA1 that are responsible for maintaining genomic stability and facilitating DNA repair. This study has implications for the treatment, diagnosis and development of therapies for patients with breast and ovarian cancer.

“Our findings suggest that caution should be exercised when targeting BRCA1 for breast and ovarian cancer therapies,” says Valerie, co-leader of the Radiation Biology and Oncology program and a professor in the Department of Radiation Oncology at VCU Massey Cancer Center. “We need to better understand the biological mechanisms that lead to the development of breast and ovarian cancer before we attempt to attack it through targeted therapies aimed at causing DNA damage.”

When DNA damage occurs, various forms of BASC (BRCA1-associated genome surveillance complex) bind to the BRCT domain on BRCA1. BASC is a protein complex that in part binds to the BRCT domain and serves as a “docking site” for other proteins and enzymes to come in, effectively repair the DNA damage and leave when repair is completed. However, certain BRCT mutants unable to bind to BASC disrupt the delicate DNA repair process. Previously, it was assumed this meant that BRCA1 was unable to assist with the repair process and, thus, recombination did not occur.

Valerie and his colleagues showed through experiments with cultured breast cancer cells and tissue samples from breast cancer patients that BRCT mutants increased ubiquination of BASC, which, in turn, increased recombination several-fold over normal levels. Ubiquitin is a small protein in all living organisms that “marks” other proteins for degradation or, as more recently discovered, the participation in specific cellular processes such as recombination. The researchers proposed that the hyper-recombination resulting from increased ubiquination of the BASC might result in improperly repaired DNA and increased genomic instability, which could lead to the development and aggressive progression of breast and ovarian cancers.

“Our results point to ubiquitination as a potential therapeutic target,” says Valerie. “By disrupting ubiquitination we may be able to prevent hyper-recombination and stop the growth of cancer cells with these BRCT mutations. This might sensitize the cancer cells to radiation therapy while having little effect on cells with normal BRCA1 function.”

The researchers hope to continue studying the role of BRCA1 in DNA double-strand break repair in order to determine whether the mutations they examined are important for the onset of cancer and whether targeted therapies can be developed.

###

The full manuscript of this study is available online at: http://www.impactaging.com/papers/v3/n5/abs/100325a.html.

Valerie collaborated on this study with Seth M. Dever, Ph.D., Sarah E. Golding, Ph.D., Elizabeth Rosenberg, M.S., Bret R. Adams, Michael O. Idowu, M.D., M.P.H., John M. Quillin, Ph.D., C.G.C., Nicholas Valerie, and Lawrence F. Povirk, Ph.D., from Virginia Commonwealth University, and Bo Xu, M.D., Ph.D., from The Methodist Hospital in Houston, Texas.

Funding for this study was provided by the National Institutes of Health.

PET scans confirm effectiveness of estrogen-blocking drugs in breast cancer patients

Posted on by
Reply

SEATTLE – For the first time, researchers at Seattle Cancer Care Alliance have demonstrated the feasibility of using serial positron emission tomography (PET) scans, using a special estrogen-containing isotope, to confirm the relative effectiveness of estrogen-blocking and estrogen-depleting therapy in patients with metastatic breast cancer. The results of the research are published online in Clinical Cancer Research.

The PET scans, taken before, during and after hormonal therapy, confirmed the superior effectiveness of estrogen-receptor-blocking drugs such as tamoxifen and fulvestrant over estrogen-depleting therapies such as aromatase inhibitors in blocking the estrogen receptor in cancer cells. The study also confirmed that tamoxifen is superior to fulvestrant in blocking estrogen.

While the results were expected they had never before been proven, according to corresponding author Hannah Linden, M.D., a breast oncologist at SCCA and an associate professor of Medicine at the University of Washington School of Medicine.

Linden and colleagues measured regional estrogen-receptor blocking and binding by using PET scans with 18F-flouroestradiol (FES), a trace amount of estrogen in isotope form, prior to and during treatment with aromatase inhibitors, tamoxifen and fulvestrant in a series of 30 patients whose breast cancer had spread to the bones. Tumor FES uptake declined more markedly in patients who took estrogen-receptor blockers compared to those who took estrogen-depleting aromatase inhibitors (an average decline of 54 percent versus 15 percent, respectively). Among the two estrogen-blocking drugs studied, the rate of complete tumor blockade was highest following use of tamoxifen versus fulvestrant.

“What we’re suggesting in the paper — that we couldn’t fully test for before — is if estrogen is incompletely blocked you’re not getting a good outcome for the patient,” Linden said.

“Our findings support the ability of FES PET to visualize the in vivo activity of endocrine therapy,” the authors concluded. “This technology could be used early in drug development to measure effectiveness at the intended therapeutic targets, and to help refine selection and dosing for agents to move forward in drug development.”

Additionally, pharmacodynamic imaging could provide clinicians with a promising tool for therapeutic selection and for predicting and evaluating response to estrogen-receptor-targeted therapy, Linden said.

###

The isotope was manufactured by the chemistry group at the UW as part of the UW Nuclear medicine program project grant. Key collaborators in the study include David Mankoff, M.D., Jeanne Link, M.D., and Kenneth Krohn, M.D., at the SCCA, and UW, and Brenda Kurland, a statistician at Fred Hutchinson Cancer Research Center. .

Grants to Linden, Mankoff and Krohn from The National Institutes of Health and the Mary Kay Ash Foundation funded the study.

Breast Feeding & Breast Cancer in African-American women

Posted on by
Reply

Investigators from the Boston University’s Slone Epidemiology Center have reported findings that may shed light on why African American women have a disproportionately higher risk of developing more aggressive and difficult-to-treat breast cancers, specifically estrogen and progesterone receptor negative (ER-/PR-) cancers.

The study, which appears online in Cancer Epidemiology, Biomarkers & Prevention, found that high parity (giving birth to two or more children) was associated with an increased risk of ER-/PR- cancer, but only among women who had not breastfed.

The findings were based on the ongoing Black Women’s Health Study, which has followed 59,000 African American women by biennial questionnaire since 1995.

In 14 years of follow-up, 318 women developed breast cancers negative for estrogen and progesterone receptors (ER-/PR-), while 457 developed breast cancers with estrogen and progesterone receptors (ER+/PR+). Giving birth to two or more children was associated with a 50 percent increase in the incidence of ER-/PR- breast cancer, but the association was not present among women who had breastfed.

According to the researchers, the results for ER+/PR+ breast cancer, which is more common among white women, were strikingly different. High parity was associated with a decreased risk, and breast feeding had no influence on that association.

“The higher incidence of ER-/PR- breast cancer in African American women may be explained in part by their higher parity and lower prevalence of breastfeeding relative to white women,” explained lead author Julie Palmer, ScD, MPH, a senior epidemiologist at the Slone Epidemiology Center and a professor of epidemiology at Boston University School of Public Health.

“Our results, taken together with recent results from studies of triple negative and basal-like breast cancer, suggest that breastfeeding can reduce risk of developing the aggressive, difficult-to-treat breast cancers that disproportionately affect African American women,” she said.

###

This study was supported by a grant from the National Cancer Institute of the National Institutes of Health.

Report: NSAIDS reduce the severity of postpartum breast cancers in animal models

Posted on by
Reply

Published online on Aug. 7, 2011, the journal Nature Medicine reports that non-steroidal anti-inflammatory drugs including ibuprofen reduce the severity of postpartum breast cancers in animal models. “We caution patients and providers that because a mother’s body is undergoing radical changes during this time, we can’t yet speak to the safety of these drugs for women diagnosed with or at risk for postpartum breast cancer, and thus can’t yet recommend NSAIDs as a preventative therapy or cancer treatment,” says Pepper Schedin, PhD, investigator at the University of Colorado Cancer Center and professor in the division of medical oncology at the University of Colorado School of Medicine, who teamed up on this study with Virginia Borges, MD, an expert in young women’s breast cancer who is also at the Cancer Center. First authors of this important paper are University of Colorado trainees, Drs. Traci Lyons and Jenean O’Brien.

The story starts with breast involution – the process by which milk-producing cells that are no longer needed are killed and replaced with fat cells. During this time of change, the breast is especially susceptible to the development of cancer. In fact, recent studies show that women who have children before age 30 increase their risk of pre-menopausal breast cancer by 10% and women who wait to have children until after age 35 increase their risk by 30%. Not only is breast cancer more prevalent in young mothers than women who have not had a child, but cancers diagnosed in the early years postpartum tend to be more aggressive, with increased risk of spreading to other organs.  For example, one study reported that women diagnosed with cancer within two years of giving birth had a 40% five-year survival rate, as opposed to a 70% five-year survival rate for women diagnosed outside the postpartum window.

What this University of Colorado research team discovered is that breast involution shares similarities with wounds, and wounds can cause cells to become cancerous in addition to promoting metastasis of otherwise localized tumor cells. Two wound-like changes that occur in the postpartum breast are an increase in fibrous collagen (the protein that gives our flesh structure) and increase of an enzyme called COX-2.

In addition to causing inflammation and pain, COX-2 aids the formation of fibrous collagen, which in the process of wound healing serves as a highway along which healthy skin cells travel in order to close the wound. However, this collagen also forms a rich architecture for the growth and spread of cancers. In short, breast involution leads to COX-2, which leads to fibrous collagen, which promotes the release of more COX-2, and this positive feedback loop can help a tumor grow and push into other tissues.

It’s a vicious chain, but one with a weak link: many drugs exist that inhibit COX-2. These include the non-steroidal anti-inflammatories (NSAIDs), such as ibuprofen, or celecoxib, which is a more targeted COX-2 inhibitor used in other inflammatory diseases like arthritis. “Inhibition of COX-2 slows the formation of fibrillar collagen and thus both tumor growth and the tumor’s travel into the lung,” write Schedin and collaborators. Sure enough, Schedin and the research team found that in postpartum mice, ibuprofen and celecoxib treatment reduced mammary tumor size, collagen architecture, COX-2 expression, and breast tumor cell spreading into the lung.

However, recommending ibuprofen for women undergoing breast involution is premature.  Schedin and Borges point out that early studies of vitamin A in lung cancer and vitamin E in prostate cancer at first found the vitamins to be cancer-fighting but eventually showed them to be cancer-promoting. “It becomes a numbers game,” says Borges, “with the benefit of the drug weighed against its dangers. It seems as if the safety of these drugs is self-evident, but it’s only because we don’t fully understand the effects of NSAIDs during this unique period of a woman’s life, when her body is undergoing dramatic changes. So it becomes very important to study the effects of NSAID treatment in this particular group of women before we can make any prevention recommendations.”

This is about the fifth step down an extremely promising path toward identifying a simple, inexpensive, effective treatment of postpartum breast cancers. But there are many steps still to go.

 —

Supported by Department of Defense Synergistic Idea Award #BC060531, Komen Foundation #KG090629, Mary Kay Ash Foundation #078-08 and University of Colorado Cancer Center grants to PS and VB, Department of Defense Award #BC074970 to PJK, American Cancer Society New England Division Postdoctoral Fellowship Spin Odyssey #PF-08-257-01-CSM to TRL, Department of Defense Postdoctoral grant BC087579 to AM, and Department of Defense Predoctoral Grant #BC073482 to JO.

New Breast Cancer Strategies Presented at Conference

Posted on by
Reply

ORLANDO, Fla. — August 3, 2011 — In their lifetime, women have more than a 12 percent risk of being diagnosed with breast cancer. 1 This week, research on novel approaches to breast cancer treatment is being presented at the Era of Hope (EOH) conference, a scientific meeting hosted by the Department of Defense Breast Cancer Research Program (BCRP).

Existing breast cancer treatments don’t work for everyone, and alternative methods and delivery systems for breast cancer treatment are critical to saving and improving patient lives. New approaches to be presented at Era of Hope include research that explores using reconstituted “good” cholesterol as a drug delivery model as well as a study looking at a heat-activated drug delivery system using peptides to target tumors.

“The Department of Defense Breast Cancer Research Program is proud to support the investment into early and new science that can potentially improve and enhance the lives of breast cancer patients,” said Captain Melissa Kaime, M.D., Director of the Congressionally Directed Medical Research Programs (CDMRP), under which the BCRP is managed. “The Era of Hope conference provides an opportunity for investigators to share the results of their research and collaborate about next steps, ultimately striving to make a significant impact in the lives of breast cancer patients.”

Thermally Targeted Delivery of a c-Myc Inhibitory Peptide in Vivo Using Elastin-like Polypeptide


Principal Investigator: Gene Leflore Bidwell, III, PhD, University of Mississippi Medical Center

Surgery, along with chemotherapy and radiation are traditional treatment methods for breast cancer, but the harm to normal tissue, tumor metastasis and resistance to treatment can hinder a successful outcome. Thus, it is critical to identify alternative targeted approaches that reduce undesired side effects. Researchers at the University of Mississippi Medical Center developed a polypeptide (CPP-ELP-H1) that is responsive to heat and inhibits breast cancer cell growth by blocking the activity of c-Myc, an oncogenic protein.

The polypeptide is comprised of cell-penetrating peptide (CPP) and elastin-like peptide (ELP). When administered systemically, ELPs remain soluble and are cleared from circulation at normal body temperature. But at the tumor site, where mild heat is applied externally, ELP aggregates and accumulates. The CPP then facilitates entry into the tumor cells, where H1, an inhibitory peptide, blocks c-Myc activity.

Researchers administer the therapeutic peptide attached to the thermally responsive ELP carrier systemically by IV injection. The heating and cooling process is repeated several times, and each time more drug carrier accumulates in the heated tumor tissue and enters the tumor cells. The net result is called “thermal targeting.” In the study’s mouse breast cancer models, investigators noticed up to three times more drug in a heated tumor relative to an unheated one, following injection of the same amount of drug intravenously. At the dose used with mice, there was a 70 percent reduction of tumor volume when using thermal targeting compared to unheated controls or controls lacking the H1 peptide. For use in the human clinical setting, mild focused heat can be applied using a technique called high intensity focused ultrasound (HIFU). This technology is rapidly developing and is actively researched by other groups. In its most sophisticated form, the HIFU technology is combined with imaging via MRI. HIFU can be used for “image guided” delivery of the heat to much defined target volumes, and MRI can accurately monitor the tissue temperature.

“What’s novel about our work is we’re developing a carrier for peptide therapeutics,” said Dr. Gene Leflore Bidwell of University of Mississippi Medical Center. “Peptides are easier to rationally design for a specific target than small molecules are. You can design peptides to modulate pathways of interest for certain types of breast cancer, but the problem with peptides is they need carriers to be made into good drugs. We generated a carrier to do that using thermal targeting, so the carrier we use specifically responds to heat.”

Selectively Targeted Therapeutics for Breast Cancer


Principal Investigators: Andras Lacko, PhD and Nirupama Sabnis, PhD, University of North Texas Health Science Center, Fort Worth

In the United States, six percent of women with breast cancer already have metastatic disease at the time of diagnosis.2 Despite improved response rates to currently available treatments, drug resistance continues to be an issue. A multi-site study was conducted to investigate a highly innovative approach for selectively targeting breast cancer by using biocompatible nanoparticles.

Researchers developed a novel drug delivery model utilizing synthetic and reconstituted high-density lipoprotein (rHDL) or good cholesterol nanoparticles that is uniquely effective in selectively encouraging cancer cells to accept therapeutic treatments. The anti-cancer agent used in the study was siRNA directed against the STAT-3 transcription factor and focal adhesion kinasse (FAK). 3 The drug carrying the nanoparticles was 20 times more efficient in suppressing the growth of breast cancer cells than the drug on its own, and in vivo studies in mice led to the suppression of the growth of human breast tumors by more than 70 percent. The system targets malignant cells and tumors via the scavenger receptor type B1 (SR=B1). The normal function of the SR-B1 receptor includes the extraction of cholesteryl esters from high density lipoproteins (HDL). This receptor has been shown to be markedly overexpressed in malignant cells and tissues, apparently because of their need for excess cholesterol due to their high proliferative rates. Researchers have found the SR-B1 receptor is also the major gateway for the entry of anti-cancer drugs into malignant cells. During the study, the accumulation of the siRNA (delivered via the rHDL nanoparticles) was undetectable in nearly all normal tissues, while it was substantial in tumor tissue, suggesting the selective drug delivery to tumors via rHDL is feasible.

“This novel drug delivery system has the potential to be compatible with most of the commonly used chemotherapy agents,” said Dr. Andras Lacko of University of North Texas Health Science Center, Fort Worth. “This is a selectively targeted model, so cancer cells are reached, and normal cells are spared. We hope to contribute to what could bring patients a more effective therapy with reduced side effects.”

Therapeutic Eradication of DCIS Progenitor Cells


Principal Investigator: Lance A. Liotta, MD, PhD, George Mason University

The true malignant nature of ductal carcinoma in situ (DCIS), breast cancer that begins inside the milk ducts 4, remains unclear, and therefore, it is often considered difficult to treat. A collaborative study led by Dr. Lance A. Liotta of George Mason University with Dr. Kirsten Edmiston of Inova Health System and Virginia Espina of George Mason University was conducted to answer the question: When does the propensity for breast cancer invasion first begin? Researchers also sought to investigate the potential of autophagy, a cell survival mechanism used by DCIS malignant progenitor cells growing within the breast duct, as a novel target for treating this type of disease.

In this study, an initial culture sample of fresh human DCIS lesions was shown to elicit cells with full malignant, or cancerous, properties in an animal model. Some of these cancerous properties include invasion, spheroid formation, and the ability to produce more tumors or tumorigenicity. Treatment with a lysosomotropic inhibitor of autophagy (chloroquine phosphate [CQ]) reversed all the invasive and tumorigenic properties, induced cell death and eliminated genetically abnormal cells from the organ culture.5 The mechanism of the suppression was the inhibition of autophagy. Findings indicate that the malignant cells are surviving within the breast duct by using autophagy to digest cell components in lysosomes and generate energy.6 Lysosomotropic inhibitors 7 work by modifying lysosomal function and reducing the cell survival mechanisms employed by malignant cells.

“Based on our findings, we are testing the safety and effectiveness of CQ in patients with DCIS,” said Dr. Lance Liotta. “This trial will investigate the applicability of autophagy as a novel treatment target for DCIS, and if successful, could provide a neoadjuvant therapy option for this difficult to treat disease and a new approach to prevent breast cancer by killing preinvasive lesions.”

Potential Links between Maternal Diet in Pregnancy and Breast Cancer in Daughters

Posted on by
Reply

ORLANDO, Fla. — August 3, 2011 — During pregnancy, women are counseled to refrain from consuming certain types of foods, beverages and medications in order to avoid jeopardizing the health and development of the fetus. In fact, the American Pregnancy Association has a list of a dozen items they recommend expectant mothers omit from their diets. However, there are some additions, such as folic acid, that, when taken before and/or during pregnancy, can actually reduce the risk of birth defects and other disorders.1 Research presented today at the Era of Hope conference, a scientific meeting hosted by the Department of Defense Breast Cancer Research Program (BCRP), reveals findings suggesting that if an expectant mother increases her consumption of foods high in certain fatty acids or nutrients during her pregnancy, she can potentially reduce the risk of breast cancer in her female offspring.

The research delves into breast cancer risk reductions attributed to the fetus when the mother, while pregnant, increases omega 3 fatty acids within her diet or consumes dietary methyl nutrients (methionine, choline, folate and vitamin B12). Some findings hypothesize that these diet augmentations may even prevent breast cancer from ever developing in the offspring.

“This is exciting and intriguing research,” said Captain Melissa Kaime, M.D., Director of the Congressionally Directed Medical Research Programs (CDMRP), under which the BCRP is managed. “To be able to reduce the risk and possibly prevent this devastating disease before birth is an incredible notion; the BCRP is proud to support research with such potential.”

Maternal Consumption of Omega 3 Fatty Acids to Reduce Breast Cancer Risk in Offspring


Principal Investigator: Philippe T. Georgel, PhD, Marshall University

Maternal dietary alterations, including increasing the consumption of omega 3 fatty acids, may reduce the risk of breast cancer to the fetus by causing epigenetic changes in utero and later through nursing. These changes may alter gene expression permanently, a change referred to as imprinting. Researchers at Marshall University conducted a study to investigate whether having a diet rich in omega 3s while pregnant would result in changes to fetal mammary gland gene expression, thereby reducing the chance that female offspring would later develop breast cancer.

In this study, there was a reduced incidence of mammary gland cancer observed for the offspring of mice that, while pregnant and nursing, consumed a diet containing canola oil, rich in omega 3, compared with the offspring of mice that, while pregnant and nursing, consumed a diet containing corn oil rich in omega 6 fatty acids. Reviewing the gene expression profiles of both groups showed that many genes related to cancer development differed between the two groups. Significant differences in the patterns of two important epigenetic markers were also observed.

“Pregnant women should be mindful of what they consume since their diet may incite epigenetic changes that could impact the development of their offspring, not just in utero but also for time to come,” said Dr. Philippe Georgel, Marshall University. “Additional research continues, as we seek to elucidate the effect of diet on breast cancer-specific gene expression.”

In Utero Exposure to Dietary Methyl Nutrients and Breast Cancer Risk in Offspring

Principal Investigator: Chung S. Park PhD, North Dakota State University

Links are being drawn to complete mammary gland development of the mother during pregnancy and reduction in breast cancer risk in her daughters. Supplementing the mother’s diet with lipotropic nutrients (methionine, choline, folate and vitamin B12) is thought to increase methyl metabolism which stimulates the full development of the mammary gland, thereby inducing an epigenetic imprint in the mammary gland of the fetus and decreasing its breast cancer risk. Investigators at North Dakota State University are researching this link with the overall objective of determining the extent to which supplementing diets with methyl nutrients during pregnancy reduces the offspring’s overall breast cancer susceptibility.

The study looked at 45 pregnant rats and randomized them into two groups: one to receive a control and the other to be fed a methyl-supplemented diet. Once the pups were born, they were separated into three additional groups depending on the feeding regime of their mother. When the female pups reached a specific age, they were exposed to a chemical that induced breast cancer and researchers charted when the first tumor appeared and measured all tumor sizes and volumes. Results demonstrated that the offspring from the methyl-supplemented diet group showed a decrease in tumor incidence and growth when compared to the control group. Also, they had fewer tumors and fewer tumors that multiplied.

“The conclusions of this study suggest that we may be able to prevent the development of breast cancer in daughters of women at risk for breast cancer by supplementing the mother’s diet during pregnancy,” said Dr. Chung Park, North Dakota State University. “We look forward to exploring this study further to strengthen the implications of these initial findings.”

Exploring Breast Cancer Mechanisms of Spread and Treatment Options

Posted on by
Reply

ORLANDO, Fla. — August 3, 2011 — Research into new methods to prevent and slow metastatic breast cancer will be presented this week at the Era of Hope conference, a scientific meeting hosted by the Department of Defense Breast Cancer Research Program (BCRP). Approximately 6 percent of women with breast cancer will have metastatic disease upon diagnosis, and up to 30 percent of node-negative and 70 percent of node-positive breast cancers will relapse. 1 Common sites for breast cancer to spread are to the lungs, liver, brain and bones.

Studies presented at Era of Hope evaluate early research on a vaccine for HER2+ breast cancer that has stopped responding to treatment is entering human clinical trials later this year will also be discussed.

“New treatments for metastatic breast cancer are needed, as many patients become resistant to existing therapies,” said Captain Melissa Kaime, M.D., Director of the Congressionally Directed Medical Research Programs (CDMRP), under which the BCRP is managed. “The novel studies presented at Era of Hope explore a number of promising pathways for treatment and new targets for preventing the spread of cancer.”

Dissecting Tumor Stromal Interactions in Breast Cancer Bone Metastasis
Principal Investigator: Yibin Kang, PhD, Princeton University

Between 60 and 80 percent of late-stage breast cancer patients eventually face bone metastasis. 2 Discovering bone metastasis genes that are clinically relevant and functionally important are critical for the development of novel therapeutics for breast cancer patients.

In this study, a multidisciplinary approach was applied to analyze the molecular basis of breast cancer bone metastasis, combining tools to analyze genomic information with animal models and clinical analysis of cancer metastasis. Candidate genes, including one dependent on EGFR 3 (Epidermal Growth Factor Receptor), and a TGFb (Transforming Growth Factor-beta) target gene called Jagged1 were identified. The study revealed a network of molecular crosstalk between tumor and bone cells using Jagged1 in tumor cells, EGFR in bone cells and TGFb released from damaged bone. Such pathological tumor-host tissue interactions eventually lead to tumor expansion and bone destructions. Targeting these pathways can reduce the development of bone metastasis and provide new avenues for managing the progression of the disease to the bones.

“We are excited to have identified new genetic markers for patients at high risk for bone metastasis, which may provide additional potential targets for preventing and treating the disease,” said Dr. Yibin Kang of Princeton University.

Rapid Translation of a Novel and Potent Vaccine in HER2+ Metastatic Breast Cancer Patients


Principal Investigator: Kim Lyerly, MD, Duke Medical Center

Approximately 20 percent of breast cancers are HER2+, meaning they over-express the HER2 gene, resulting in a particularly aggressive form of the disease.4 The first targeted treatment approved to treat HER2+ breast cancer was Herceptin® (trastuzumab) — in which the BCRP provided the early funding for research leading to the development of monoclonal antibodies against the HER2 receptor. However, despite its specificity, many patients experience resistance.5 Researchers at Duke University Medical Center evaluated a novel viral vector vaccine combination for testing in trastuzumab-refractory breast cancer patients.

Viruses attack and invade host cells by injecting their DNA as part of their replication process. In vaccine development, viruses can be used in this way to bring disease-fighting genetic information inside human cells.6 In this study, the two viral vectors, an adenovirus construct (Ad-HER2) and an alphavirus VRP construct (VRP-HER2), when used together in animal models have shown to elicit potent immune responses capable of halting the growth of and directly killing human breast cancer cells that are resistant to trastuzumab. Duke researchers, in seeking to prepare and submit an Investigational New Drug (IND) application for the U.S. Food and Drug Administration (FDA), have demonstrated through preclinical research that the vaccine is potent, does not cause tumor development, and is compatible with lapatinib, another treatment specifically targeting HER2+ breast cancer. Both viral vectors are currently undergoing preclinical toxicology studies and are expected to enter the clinic in the third quarter of 2011.

“Patients with HER2+ breast cancer often face the reality of relapse,” said Dr. Kim Lyerly of Duke University Medical Center. “We are excited about continuing this translational-based, cutting-edge vaccine strategy, and potentially bringing them a new way to fight the disease.”

Combining dasatinib with Tamoxifen, may overcome Tamoxifen resistance in breast cancer

Posted on by
Reply

August 1 20100

PHILADELPHIA—Taking a leukemia chemotherapy drug may help breast cancer patients who don’t respond to tamoxifen overcome resistance to the widely-used drug, new research from the Kimmel Cancer Center at Jefferson suggests.

Interestingly, researchers found that taxoxifen combined with dasatinib, a protein-tyrosine kinase inhibitor, reverses the chemo-resistance caused by cancer-associated fibroblasts in the surrounding tissue by normalizing glucose intake and reducing mitochondrial oxidative stress, the process that fuels the cancer cells.

Previous animal studies have confirmed that combining tyrosine kinase inhibitors with anti-estrogen therapies, like tamoxifen, can prevent drug resistance, but none have suggested that the target of the inhibitors is the cancer-associated fibroblasts.

The researchers report their findings in the August 1 issue of Cell Cycle.

About 70 percent of women diagnosed with breast cancer will have estrogen receptor positive (ER(+)) disease, which indicates that the tumor may respond to tamoxifen. However, a large percentage of these tumors—up to 35 percent—have little to no response to the drug or eventually develop resistance to it.

In this study, researchers sought to better understand drug resistance by looking at the metabolic basis in an ER (+) cell line and cancer-associated fibroblasts. The researchers have previously established a relationship between the two, where cancer cells induce aerobic glycolysis by secreting hydrogen peroxide in adjacent fibroblasts via oxidative stress. In turn, these fibroblasts provide nutrients to the cancer cells to proliferate, a process that ultimately makes tumors grow.

Here, they investigated and then demonstrated that this interaction was also the basis of tamoxifen resistance.

In a sense, the drug combination had an “antioxidant effect” in these types of cancer cells, according to Michael P. Lisanti, M.D., Ph.D., Professor and Chair of Stem Cell Biology and Regenerative Medicine at Jefferson Medical College of Thomas Jefferson University and a member of the Kimmel Cancer Center.

“The fibroblasts are what make ER (+) cancer cells resistant to the tamoxifen,” said Dr. Lisanti. “But the tamoxifen plus dasatinib maintained both fibroblasts and cancer cells in a ‘glycolytic state,’ with minimal oxidative stress and more cell death, most likely because of an absence of metabolic coupling. The supply between the two was cut.”

“This suggests resistance to chemotherapeutic agents is a metabolic and stromal phenomenal,” he added.

Researchers showed that ER (+) cancer cells alone responded to tamoxifen but when co-cultured with human fibroblasts had little to no effect. Similarly, dasatinib, a chemotherapy drug used to treat leukemia patients who can no longer benefit from other medications, had no effect on fibroblasts alone or cancer cells. Together, however, the drugs prevented the cancer cells co-cultured with the fibroblasts from using high-energy nutrients from the fibroblasts.

This combination resulted in nearly 80 percent cell death, the team reported—a two to three fold increase when compared with tamoxifen alone.

“The drugs have no effect when they are used alone—it’s in unison when they effectively kill the cancer cells in the presence of fibroblasts,” said Dr. Lisanti. “This opens up the door for possible new treatment strategies. This ‘synthetic lethality’ may help patients overcome resistance in the clinic.”

Study examines how blood protein levels change as breast cancer develops before it is clinically detectable

Posted on by
Reply

SEATTLE – Using a “systems biology” approach – which focuses on understanding the complex relationships between biological systems – to look under the hood of an aggressive form of breast cancer, researchers for the first time have identified a set of proteins in the blood that change in abundance long before the cancer is clinically detectable. The findings, by co-authors Christopher Kemp, Ph.D., and Samir Hanash, M.D., Ph.D., members of Fred Hutchinson Cancer Research Center’s Human Biology and Public Health Sciences divisions, respectively, are published online ahead of the Aug. 1 print issue of Cancer Research.

Studying a mouse model of HER2-positive breast cancer (cancer that tests positive for a protein called human epidermal growth factor receptor 2) at various stages of tumor development and remission, the researchers found that even at the very earliest stages the incipient tumor cells communicate to normal tissues of the host by sending out signals and recruiting cells, while the host tissues in turn respond to and amplify the signals.

“It is really a ‘systems biology’ study of cancer, in that we simultaneously examined many genes and proteins over time – not just in the tumor but in blood and host tissues.” Kemp said. “The overall surprising thing we found was the degree to which the host responds to cancer early in the course of disease progression, and the extent of that response. While a mouse – or presumably a human – with early-stage cancer may appear normal, our study shows that there are many changes occurring long before the disease can be detected clinically. This gives us hope that we should be able to identify those changes and use them as early detection tools with the ultimate goal of more effective intervention.”

Traditionally, it has been thought that tumor cells shed telltale proteins into the blood or elicit an immune response that can lead to changes in blood-protein levels. “What is new here is that the predominant protein signals we see in blood originate from complex interactions and crosstalk between the tumor cells and the local host microenvironment,” Kemp said.

Until now, such tumor/host interactions have been primarily studied one gene at a time locally, within the tumor; this is the first study to monitor the systemic response to cancer in a preclinical tumor model, tracking the abundance of cancer-related proteins throughout tumor induction, growth, and regression. Of approximately 500 proteins detected, up to a third changed in abundance; the number increased with cancer growth and decreased with tumor regression.

“We found a treasure trove of proteins that are involved in a variety of mechanisms related to cancer development, from the formation of blood vessels that feed tumors to signatures of early cancer spread, or metastasis,” Kemp said.

Proteins associated with wound repair were most prevalent during the earliest stages of cancer growth, which could point to a potential target for early cancer detection. “Rather than blindly search for cancer biomarkers, an approach based on comprehensive understanding of the systems biology of the disease process is likely to increase the chances to identify blood-based biomarkers that will work in the clinic,” Kemp said.

The next steps will involve selecting the most promising protein candidates found in mice and determining whether the same circulating proteins are markers of early breast cancer development in humans, with the ultimate goal of designing a blood test for earlier breast cancer detection.

###

The Paul G. Allen Family Foundation, the National Cancer Institute Mouse Models of Human Cancer Consortium and the Canary Foundation funded the research.

Breast density tied to specific types of breast cancer

Posted on by
Reply

Women with breasts that appear dense on mammograms are at a higher risk of breast cancer and their tumors are more likely to have certain aggressive characteristics than women with less dense breasts, according to a study published online July 27 in the Journal of the National Cancer Institute.

Mammographic breast density–a reflection of the proportions of fat, connective tissue, and epithelial tissue in the breast–is a well-established risk factor for breast cancer. Women with higher amounts of epithelial and stromal tissue have higher density and higher risk. However, it has not been clear whether breast density was associated with specific tumor characteristics and tumor type.

To explore this issue, Rulla M. Tamimi, Sc.D., at Harvard Medical School and Brigham and Women’s Hospital, Boston, and colleagues, compared breast density in 1,042 postmenopausal women with breast cancer and 1,794 matched control subjects (women who were similar in terms of age, postmenopausal hormone use, and other factors, but did not have breast cancer).

The researchers found, as expected, that the risk of breast cancer increased progressively with increasing breast density. The associations were stronger for larger tumors than for smaller tumors; for high-grade than for low-grade tumors; and for estrogen receptor-negative than for estrogen receptor-positive tumors. The link between density and breast cancer also appeared to be stronger for ductal carcinoma in situ (DCIS) than for invasive tumors. There was no association, however, between density and other markers of tumor aggressiveness, such as nodal involvement and HER2 status.

The authors conclude that higher mammographic density is associated with more aggressive tumor characteristics and also with DCIS. “Our results suggest that breast density influences the risk of breast cancer subtypes by potentially different mechanisms,” they write. “Further studies are warranted to explain underlying biological processes and elucidate the possible pathways from high breast density to the specific subtypes of breast carcinoma.”

An accompanying editorial agrees that understanding the biological links between breast density and specific tumor subtypes could help us understand more about breast cancer risk and the molecular causes of breast cancer. Karla Kerlikowske, M.D., of the University of California, San Francisco and Amanda Phipps, Ph.D., of Fred Hutchinson Cancer Research Center in Seattle emphasize that this large study was the first to find a stronger association between breast density and ER-negative tumors than ER-positive tumors.

They caution, however, that this stronger association might be due, in part, to the ‘masking effect.’ “Masking of a tumor can occur because cancerous tissue and mammographically dense tissue have similar x-ray attenuation, allowing tumors to go undetected on screening mammography examination and progress to a more advanced and aggressive stage before detection,” they write. In this study, it is not known whether the tumors were detected by screening mammography. The editorialists also discuss other possible reasons for the strong link between density and aggressive tumors, including the interaction of increased numbers of stromal and epithelial cells in dense breasts and exposure to postmenopausal hormones.

They conclude that breast density is an important risk factor for diverse subtypes of breast cancer. “Given that the magnitude of the association with breast density is strong across all breast cancer subtypes and particularly for ER-negative disease, breast density should be included in risk prediction models across tumor subtypes,” they write.