In Utero Exposure to Ethinyl Estradiol Linked to Tamoxifen Resistance and Breast Cancer Recurrence

MedicalResearch.com Interview with:

Leena Hilakivi-Clarke, PhD Professor of Oncology Georgetown University Washington, DC 20057

Dr. Leena Hilakivi-Clarke

Leena Hilakivi-Clarke, PhD
Professor of Oncology
Georgetown University
Washington, DC 20057

MedicalResearch.com: What is the background for this study?

Response: About 70% of women who develop breast cancer express estrogen receptors in their cancer. These patients are treated with endocrine therapies that target estrogen receptors. Endocrine therapies are effective in half of the patients, but the other half are resistant to the treatment and recur. Prior to the start of endocrine therapy, there is no way to predict who will respond to it and who will have recurrence of breast cancer. Therefore, it is not known which patients might benefit from an additional therapy to prevent recurrence, and what that additional therapy would entail. We wondered if resistance to endocrine therapy (we used tamoxifen) is pre-programmed by maternal exposure to the estrogenic endocrine disrupting chemical ethinyl estradiol (EE2). Previously, we and others have found that EE2 and other estrogenic compounds, when given during pregnancy, increase breast cancer risk in the female offspring in animal studies and among humans. The current study was done using a preclinical animal model that was used 50 years ago to discover that tamoxifen is an effective endocrine therapy for estrogen receptor positive breast cancer patients.

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Breast Cancer: Gene Mediating Tamoxifen Resistance Identified

Ben Ho Park, M.D., Ph.D. Associate Professor of Oncology, Breast Cancer Program Associate Director, Hematology/Oncology Fellowship Training Program The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, MD  21287MedicalResearch.com Interview with:
Ben Ho Park, M.D., Ph.D.
Associate Professor of Oncology, Breast Cancer Program
Associate Director, Hematology/Oncology Fellowship Training Program The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, MD  21287

Medical Research: What is the background for this study? What are the main findings?

Dr. Park: To discover genetic mediators of tamoxifen resistance in breast cancers, we used genetic screening of breast cancer cell line models and patient data to ​identify a new gene that can mediate drug resistance. We found that amplification and overexpression of this gene in estrogen receptor positive breast cancers results in tamoxifen resistance and is associated with worse outcomes in patients whose tumors demonstrate amplification/overexpression of this gene.

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Night Light May Drive Breast Cancer Growth

MSteven M. Hill, Ph.D. Professor, Structural & Cellular Biology Edmond & Lily Safra Chair for Breast Cancer Research Co-Director, Molecular Signaling Program, Louisiana Cancer Research Consortium Director, Tulane Circadian Biology CenteredicalResearch.com Interview with
Steven M. Hill, Ph.D.
Professor, Structural & Cellular Biology
Edmond & Lily Safra Chair for Breast Cancer Research
Co-Director, Molecular Signaling Program, Louisiana Cancer Research Consortium
Director, Tulane Circadian Biology Center

Medical Research: What are the main findings of the study?

Dr. Hill: The main findings of our study are that exposure to even dim light at night can drive human breast tumors to a hyper metabolic state, activating key tumor cell signaling pathways involved in tumor cell survival and proliferation, leading to increased tumor growth, all resulting in a tumor which is completely resistant to tamoxifen therapy. Our work shows that this effect is due to the repression of nighttime melatonin by dim light at night. When nighttime melatonin is replace the tumors become sensitive to tamoxifen resulting in cell death and tumor regression.
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Breast Cancer: Does Tamoxifen Affect Cognitive Function in Postmenopausal Women?

Florien Boel MSc VU University Medical Center Department of Medical Psychology Amsterdam, The Netherlands MedicalResearch.com Interview with:
Florien Boel MSc
VU University Medical Center
Department of Medical Psychology
Amsterdam, The Netherlands


Medical Research: What are the main findings of the study?

Answer: In postmenopausal breast cancer patients, endocrine therapy is widely used, and often for many years on end. Endocrine therapy is thought to have an effect on cognitive functioning, but previous studies have not yet accounted for the possible influence of the diagnosis of cancer and subsequent anxiety, depression or fatigue on cognitive performance. In addition, the cognitive effects of endocrine therapy after long-term use are still mostly unknown.

Therefore, we compared cognitive functioning of postmenopausal breast cancer patients who underwent surgery and/or radiotherapy (N=43) with the cognitive performance of women who also received adjuvant endocrine therapy (tamoxifen) (N=20) and a group of healthy matched individuals (N=44). In accordance with the literature, we found that especially cognitive domains that rely heavily on verbal abilities (verbal memory and fluency) seem to be at risk for deterioration during long-term treatment (~2.5 years) with tamoxifen.
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Premenopausal Breast Cancer: Exemestane Found Superior to Tamoxifen in Estrogen Positive Disease

Dr. Olivia Pagani Institute of Oncology of Southern Switzerland Ospedale San Giovanni, Switzerland
MedicalResearch.com Interview with: 

Dr. Olivia Pagani
Clinical Director of the Breast Unit of Southern Switzerland
Ospedale San Giovanni, Switzerland

Medical Research: What are the main findings of the study?

Dr. Pagani: The study showed that the aromatase inhibitor Exemestane is superior to Tamoxifen (both given together with ovarian function suppression) in preventing breast cancer recurrence in premenopausal women with oestrogen receptor positive early breast cancer.
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Tamoxifen Found in Some Dietary Supplements

Simon D. Brandt, PhD Reader in Bioactive Drug Chemistry School of Pharmacy & Biomolecular Sciences Liverpool John Moores University Liverpool, L3 3AF, UK Associate Editor "Drug Testing and Analysis" (Wiley)MedicalResearch.com Interview with:
Simon D. Brandt, PhD
Reader in Bioactive Drug Chemistry
School of Pharmacy & Biomolecular Sciences
Liverpool John Moores University
Associate Editor “Drug Testing and Analysis” (Wiley)

Author’s background comment:

This type of work represents one of our areas of activity related to multi-disciplinary approaches to harm reduction which combines public health work with research on various properties of bioactive substances.

MedicalResearch.com: What are the main findings of the study?

Answer: As part of our work related to so-called lifestyle and image-enhancing drugs and legal highs/bath salts, we became interested in a particular “food/dietary supplement” called “Esto Suppress” because it was discussed on some Internet forums dedicated to the topic of bodybuilding. Some forum members were speculating that tamoxifen might be present in this particular product. The reason for this speculation came from the chemical name that was written on the label which pointed in that direction. This particular product was also widely available from a number of online retailers and while some indications existed that the same chemical name was mentioned, others were seen to list a modified version of that name which did not always make much chemical sense. We test purchased four “Esto Suppress” samples in a local fitness store and confirmed that three of them contained the breast cancer drug tamoxifen.
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Breast Cancer: Surgical Oophoretomy + Tamoxifen – Impact on Bone Loss

Richard R. Love, MD MS International Breast Cancer Research Foundation Professor of Medicine and Public Health The Ohio State University Columbus, OHMedicalResearch.com: Interview with:

Richard R. Love, MD MS
International Breast Cancer Research Foundation
Professor of Medicine and Public Health The Ohio State University
Columbus, OH
MedicalResearch.com: What are the main findings of the study?

Answer: Surgical oophorectomy and tamoxifen treatment was associated with no loss of bone mineral density (BMD) in the femoral neck, and loss of BMD in the first year, followed by stabilization in the lumbar spine.
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Combining dasatinib with Tamoxifen, may overcome Tamoxifen resistance in breast cancer

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.”