Scientific Program

Day 1 :

Biography:

Hiroshi Kobayashi received his Ph.D. in Biochemistry from University of Tokyo in 1974. After his postdoctoral training at Colorado University Medical Center, he started to study adaptation strategies of microorganisms to acidic environments at Chiba University in 1978. His research has been focused on mammalian cell functions under acidic conditions from 1996 at Graduate School of Pharmaceutical Sciences, Chiba University. His current challenge is to develop cancer chemotherapy specific to acidic nests. He retired in March 2012 and is now a professor emeritus at Chiba University. He works as an associate editor of International Immunopharmacology published by Elsevier B.V. from 2014.

Abstract:

Acidity in cancer nests has been investigated for over 80 years, but anti-cancer chemotherapy specific to acidic microenvironments has not been developed. Acidification of cancer nests is generally less than 2 pH units, and it has been argued that intracellular pH is not changed due to the cytosolic pH homeostasis. However, recent studies have revealed that cytosolic pH decreases with the acidification of extracellular environments, although the pH change in cytosolic space is less than that in the surroundings. For example, cytosolic pH values were reported to be 7.4 and 6.9 in media with a pH of 7.4 and 6.5, respectively. In another report, cytosolic pH values were 7.4 and 6.8 in media with a pH of 7.4 and 6.2, respectively. Many researchers had thought that such small pH changes do not affect cellular metabolisms, but the expression of many genes was found to increase under acidic conditions. These data suggest that some metabolic activities alter as the acidification of cancer nests, leading us to develop anti-cancer chemotherapy specific to acidic nests. Until now, four drugs have been found to have high efficacy to inhibit cancer progression under acidic conditions. These acidosis-dependent drugs have a great advantage to be less effective in normal tissues whose pH is slightly alkaline. On the basis of these findings, I would like to discuss the innovative chemotherapy specific to cancers progressing in acidified nests.

  • Cancer Therapy and Novel Approaches

Session Introduction

Fischer M

University Hospital Marburg/Germany

Title: Radionuclide therapy of malignant bone lesions
Speaker
Biography:

Abstract:

Radionuclide therapy in patients suffering from bone metastases is used since decades. Primarily this treatment was approved for bone pain palliation (89Strontium in bone lesions due to HRPC, 153Samarium for osteoblastic bone metastases, independently from the primary tumor). In 2013 223Radium was approved for treatment of HRPC bone metastases. A prolongation of median survival in the verum group vs. placebo group of 3.6 months was observed. β-emitting radionuclides in combination with chemotherapy may lead to a significant prolongation of median survival up to 10 months compared to patients only getting radionuclides, together with also significant improvement of pain syndrome.

More recently radiolabeled PSMA ligands are used in clinical trials and on a compassionate use basis for diagnostic procedures in various primary, mainly prostate cancer tumors as well as in therapy of those tumors expressing PSMA on the cell surface and showing sufficient tracer uptake. Studies with either 68Gallium-PSMA PET/CT or 99mTc-PSMA for diagnostic procedures and 177Lutetium-PSMA ligands for treatment of HRPC bone and soft tissue lesions are showing high sensitivity and for treatment excellent response rates given their predominant use as last line treatment. However, prospective studies are needed to define the role of this approach in the management of advanced prostate carcinoma.

  • Cancer Biology
Speaker
Biography:

Dr. Ekarat Hitakomate received his PhD in cell and molecular biology from the university of Dundee in 2010. His
PhD thesis was focusing on the molecular mechanisms of RCC1 interaction with chromatin and characterization
of its binding partners. His current research interests are biology of oral cancer and the regulation of cancer
metastasis.

Abstract:

Statement of the problem: Tongue squamous cell carcinoma (TSCC) is one of the major health concerns worldwide with high morbidity and mortality rates. Currently, effective therapeutic interventions for TSCC are limited. Therefore, identification of such molecular targets is of clinical relevance. Recent data have shown that the ribosomal protein S6 kinase, 90 kDa, polypeptide 1 (RSK1) a member of Ser/Thr protein kinases plays an important role in regulating cell invasion and metastasis in human cancers. How RSK1 play a role in TSCC remains currently unclear. The purpose of this study was to examine a function of RSK1 in TSCC proliferation, migration, and invasion of the TSCC cell line HSC-3 and its lymph node metastatic counterpart HSC-3-M3 cell line using siRNA approach. Findings: RSK1 expression was efficiently repressed using specific siRNAs compared to that of non-specific siRNA group. We found that silencing RSK1 significantly inhibited cell proliferation in both HSC-3 and HSC-3-M3 cell lines. Live cell migration of HSC-3 and HSC-3-M3 transfected with RSK1 specific siRNA was compared with that of non-specific siRNA transfected cells using live cell imaging. Inhibition of RSK1 expression in both HSC-3 and HSC-3-M3 also affected live cell migration. Importantly, silencing RSK1 interfered with invasive capacity of both HSC-3 and HSC-3-M3 cells lines. How RSK1 is involved in regulating TSCC invasiveness will be discussed. Conclusion & significance: RSK1 may play a role in promoting cell proliferation, cell migration and invasion in TSCC cell lines.

Speaker
Biography:

Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48080 Bilbao (Spain)

Abstract:

Pancreatic cancer is the fourth leading cause of cancer mortality with a 5-year survival rate of only 6%. This aggressive disease is characterized by invasiveness, rapid progression and profound resistance to treatment. Using an in vitro cell migration assay we have found that ceramide 1-phosphate (C1P) enhances human pancreatic cancer cell migration and invasion potently and that this effect is completely abolished by pertussis toxin (PTX), suggesting the participation of a Gi protein-coupled receptor in this process. Activation of the C1P receptor caused phosphorylation and activation of ERK1-2 and Akt, and inhibition of these kinases abolished C1P-stimulated cell migration/invasion. We have also observed that human pancreatic cancer PANC-1 and Mia PaCa-2 cells migrate spontaneously. Contrary to the effect of C1P, spontaneous cell migration was insensitive to treatment with PTX. Investigation into the mechanisms responsible for spontaneous migration of the pancreatic cancer cells revealed that ceramide kinase (CerK) is a key enzyme in the regulation of this process. In fact, inhibition of CerK activity with the selective inhibitor NVP-231, or treatment with specific CerK siRNA to silence the gene encoding this kinase, potently reduced migration of the pancreatic cancer cells. By contrast, overexpression of CerK stimulated cell migration, an action that was concomitant with prolonged phosphorylation of ERK1-2 and Akt, which are kinases involved in C1P-stimulated cell migration/invasion, in a PTX independent manner. It can be concluded that the axis CerK/C1P plays a critical role in pancreatic cancer cell migration/invasion, and that targeting CerK expression or activity may be a relevant factor for controlling pancreatic cancer cell dissemination.

Speaker
Biography:

Abstract:

Oral cancer is one of the eight most common cancers in the world and occurs more often in males in developing countries than developed countries. Oral precancereous lesions, a benign morphologically altered tissue that has a greater than normal risk of malignant transformation, such as leukoplakia etc., is also very common. Leukoplakia and submucous fibrosis are early indicators of damage to the oral mucosa with a transformation rate of 2-12% to frank malignancies. Μany environmental factors and genetic factors are implicated in the development of oral cancer . Several factors related to angiogenesis, inflammation and thrombosis have also been associated with oral oncogenesis. Such factors previously implicated in cancer, inflammation and thrombotic events are tumor necrosis factor alpha (TNF-α) and beta (TNF-β), which are respectively encoded by TNF-α and TNF-β genes.

TNF-α-238G/A is a proinflammatory multifunctional cytokine produced by macrophages. It plays an important role in the regulation of immune response since its increase after traumatic injury generates a cytokine cascade resulting in activation, proliferation and hypertrophy of mononuclear and phagocytic cells. TNF-α-238G/A has been implicated in the pathogenesis and progression of various malignancies. The biological activities of TNF-α-238G/A and the fact that its gene is located within the major histocompatibility complex have suggested that polymorphisms in this locus may be associated with autoimmune, infectious and neoplastic disorders. In light of the recently found contribution of inflammation-related factors to oral cancer, the possible correlation of tumor necrosis factor alpha and beta genes (TNF-α and TNF-β) with risk of oral cancer was investigated. A study was done in King George Medical University, Luck now ,India in which a total 250 patients with Oral pre cancer & cancer and 250 healthy volunteers were genotypes for the TNF-α (-238) G/A andTNF-β(-252) A/G gene polymorphism. Genotypes were identified by polymerase chain reaction (PCR) restriction fragment length polymorphism(RFLP). Genotype frequencies were evaluated by Chi-square test and Odds ratio (OR) relative risk.

TNF-α (-238) G/A, TNF-β(-252) A/G polymorphism were significantly associated with Oral pre cancer & cancer patients as compared to healthy volunteers.(GA, p=0.0050*, AG, p= 0.497*)

We found that the TNF-α (-238) G/A, TNF-β(-252) A/G polymorphism were significantly associated with Oral pre cancer & cancer.

  • Cancer Research
Speaker
Biography:

Experimental and Clinical Physiopathology Research Group CTS-1039, Department of Health Sciences, School of Health Sciences, University of Jaén, Campus Universitario Las Lagunillas, E23071 Jaén, Spain.

Abstract:

Plasma amino acid levels depend of all factors that affect the body’s amino acid flow and are tightly regulated through a continuous cycle of protein formation/degradation in order to maintain neutral protein balance. Different pathologies, including cancer, have frequently been associated with an alteration in protein metabolism and are characterized by an increase in protein exchange. In fact, the tumour cells require a greater amount of amino acids for the synthesis of new proteins and nucleic acids; therefore, changes in the circulating amino acid profile may be detected. Many studies have suggested the possibility of establishing a specific amino acid profile for each type of cancer. In addition, the influence of different compounds of diet has also been described in cancer. In the present work, we analyzed the influence of several normolipidic dietary fats (extra virgin olive oil, sunflower oil and sunflower oil enriched with oleic acid) on plasma amino acids in rats with N-methyl-nitrosourea (NMU)-induced breast cancer. It allowed us to know the changes in plasma amino acid levels in this animal model, if a specific profile of amino acid exits in this type of tumour and if dietary fat modified this profile. Our results showed significant increases in several amino acids, including aspartic acid, glutamine, glycine, 1-methyl-hystidine, 3-methyl-hystidine, ornithine, taurine and alanine in rats with NMU-induced breast cancer. Furthermore, pooled non-essential and basic amino acids were also increased in these animals. The analysis of dietary fats showed that plasma amino acid levels did not change in animals with NMU-induced breast cancer fed with extra virgin olive oil and sunflower oil, but those animals fed with oleic acid-enriched sunflower oil showed plasma amino acid levels similar to control group. These results may indicate that the establishment of a specific plasma amino acid profile for breast cancer could be influenced by external factors such as dietary fat.

Speaker
Biography:

Abstract:

Background
Cannabis plants contain more than 150 phytocannabinoids which are presumed to have bioactive properties. Yet, the identification of Cannabis components is usually limited to several species. Recently, the therapeutic potential of these phytocannabinoids has been rediscovered in cancer research as these compounds were found to have palliative effects in oncology. Moreover, there is accumulating evidence showing antitumor effects. In response to phytocannabinoids, several studies showed a regression of different tumors in vivo. Further investigations in vitro have revealed that they can induce cell death and inhibit proliferation of cancer cells. The concentrations and combinations of various phytocannabinoids determine both medicinal and adverse effects in patients. Therefore, analyzing the chemical content of differing Cannabis plants is of major importance.

The objective is to assess a variety of Cannabis preparations and to elucidate which factors are responsible for their antitumor effects, in order to better understand how Cannabis may effectively treat cancer

Methods
We perfected extraction techniques and identified distinct compositions of 12 clinically-used Cannabis strains. We then explored the differential antitumor effects of these Cannabis extracts (differing in cannabinoid compositions) on 12 cancer cell lines.

Conclusions
Categorizing cancer cells according to their response to medicinal Cannabis will provide valuable information for the development specific Cannabis treatments for subgroups of cancer patients.

 

  • Cancer Metastsis
Speaker
Biography:

Experimental and Clinical Physiopathology Research Group CTS-1039, Department of Health Sciences, School of Health Sciences, University of Jaén, Campus Universitario Las Lagunillas, E23071 Jaén, Spain.

Abstract:

Lymphatic metastasis is regulated at multiple steps including the transit of tumour cells via the lymphatic vessels and the successful seeding in draining lymph nodes. To that, several molecular signals and cellular changes must be involved in this complex process to facilitate tumour cell entry, colonization and survival in the lymph node. The present work explores the redox status (oxidative stress parameters and enzymatic and non-enzymatic antioxidant defence systems) in the sentinel lymph node (SLN) of women with breast cancer. SLN from 75 women with breast cancer were identified using the one-step nucleic acid amplification (OSNA) method as negative (n=43); with micrometastases (n=13) or with macrometastases (n=19). It will allow the knowledge about the pro-oxidant/antioxidant mechanisms involved in the processes of distant metastases in breast cancer and also to assess whether these parameters may be alternative techniques for staging. We found different levels of lipid peroxidation in SLNs with micrometastases (increased) and macrometastases (decreased), a decrease in carbonyl groups content in SLNs with macrometastases only and an increase in total antioxidant capacity (TAC) in SNLs with micrometastases and macrometastases. A decrease in the levels of reduced glutathione (GSH) also appears in the SLNs with macrometastases only. Finally, we show increased levels of superoxide dismutase (SOD) and catalase (CAT) activities in SLNs with micrometastases and macrometastases and decreased levels of glutathione peroxidase (GPx) activity in SNLs with macrometastases but not with micrometastases. We conclude that redox status of lymph node microenvironment participates in the progression of metastatic breast cancer.

  • Anticancer Drugs
Speaker
Biography:

Abstract:

The plant Conyza sumatrensis is used in traditional medicine in parts of Africa for the treatment of numerous  health ailments like inflammatation, skin diseases as well as cancers. Bioassay guided fractionation of the methanol extract of the leaves of Conyza sumatrensis against  breast cancer (MCF-7), lung cancer (NCI-H460) and NIH 3T3 (mouse embryonic fibroblast normal cell line) at 1-250 µg/mL was carried out. Fractions and isolated compounds were as well tested at 1-100 µg/mL  and 1-100 µM against the cell lines. Extracts of C.sumatrensis was partitioned into aqueous and chloroform fractions and both fractions were tested for their effects on MCF-7 and NCI-H460. Further chromatographic and biological studies of the active chloroform fraction yielded two compound whose identities were revealed as Stigmasterol 3-O-beta-D-glucoside (A)  and 2, 3-dihydroxylpropyl hexacosanoate (B) through NMR and MS studies. These compounds were observed to give –16.50 ± 0.14 and –21.71 ± 0.23 % cytotoxicities against MCF-7 at 100 µM with GI50 and TGI of 40 ± 0.10, 50 ± 6.0 µM and 22.67 ± 1.33 and 69.33 ±1.33 µM respectively. These compounds were also cytotoxic against NCI-H460 celll lines but less than doxorubicin, the anticancer drug used.The overall results showed that the plant can be used to prevent the proliferation of breast and lung cancer cells and hence justify the ethnomedicinal uses of the plants in treating tumour related ailments

Day 2 :

Keynote Forum

Ujwala Salvi

CEO, Nucleon Therapeutics

Keynote: Keynote

Time : 09:30

Biography:

Abstract:

Not yet Submitted

  • Cancer Screening

Session Introduction

Jingmei Jiang

Chinese Academy of Medical Sciences, Beijing

Title: Benefits and harms of low-dose CT screening in China: a decision analysis
Speaker
Biography:

Abstract:

Background: This study aimed to evaluate population outcomes with low-dose CT (LDCT) screening for lung cancer in urban areas of China.

 

Methods: A decision tree model with three scenarios (low-dose CT screening, chest X-ray screening, and no screening) was developed to compare screening results in a simulated Chinese urban cohort (100,000 smokers aged 45-80 years). Data of participant characteristics were obtained from national registries and epidemiological surveys for estimating lung cancer prevalence. The selection of other tree variables such as sensitivities and specificities of LDCT and chest X-ray screening were based on literature research (mainly in China). Base case and sensitivity analyses were performed to compare mortality, false positive findings, and quality-adjusted life years (QALY) in the three scenarios.

Results: In base case analysis, there were 448, 541, and 591 lung cancer deaths in the low-dose CT, chest X-ray, and no screening scenarios, respectively (17.2% reduction in low-dose CT screening over chest X-ray screening and 24.2% over no screening). LDCT screening resulted in slightly more QALYs: 147 years over chest X-ray screening and 250 years over no screening. However, in sensitive analysis, improvement in mortality was subtle or negative with LDCT (16 absolute, 5.4% relative reduction compared with no screening, −11 absolute, −4.1% reduction compared with chest X-ray) in worst case, and the gain of QALY in low-dose CT screening over no screening would diminish if screening was performed among populations with a low prevalence of lung cancer below 436 per 100,000. Besides, the costs of LDCT screening were 9387 false diagnoses (3.76 times over chest X-ray) and 7 deaths due to false diagnosis (3.50 times over chest X-ray).

 

Conclusions: Our findings favor conducting LDCT screening in urban China in terms of mortality outcome. However, approaches to reducing false diagnoses and optimizing other screening conditions are highly needed to maximize benefits and minimize harms associated with this screening device.

Speaker
Biography:

Abstract:

To be updated

  • AlternativeMedicine in Cancer
Speaker
Biography:

Abstract:

Cervical cancer is the fourth most common cause of cancer death affecting women worldwide. Every year, 528,000 new cases of cervical cancer have been reported globally. Different measures have been suggested to prevent cervical cancer. These include the use of natural plant extract which is known as Streblus asper.  Streblus asper is known to have a beneficial effect against many cancers like osteosarcoma, tongue carcinoma, mouse lymphocytic leukaemia p388 cells, and human nasopharyngeal epidermoid carcinoma (KB cell). The present study attempted to identify the key protein associated with in vivo anticancer mechanism of Streblus asper against cervical cancer. Streblus asper extract was used as drinking water at certain doses, all SCID mice were sacrificed after several weeks, and tumour tissues were analysed for protein identification and expression using label-free quantification of nano Liquid Chromatography-Mass Spectrometry (LCMS). Among 128 proteins found, four proteins were associated with 14-3-3 protein family (β isoform, γ isoform, ζ isoform, and τ isoform). 14-3-3 protein is a regulatory protein that play significant roles in signal transduction, apoptosis, cell cycle progression and DNA replication. These four isoforms of 14-3-3 protein (β, γ, ζ, τ) had been found by previous studies to be overexpressed in cancers like breast and lung. Interestingly, our bioinformatics analysis revealed that the expression of four isoforms of 14-3-3 protein were significantly downregulated following S.asper treatment. This result was validated by the combination of gel electrophoresis and protein sequencing analysis. The findings provide an insight into the role of 14-3-3 family proteins as an important biomarker for cervical cancer treatment.

  • Cancer Management and Prevention

Session Introduction

Dr. Hiroshi Kobayashi

Chiba University

Title: T cell functions under acidic conditions
Speaker
Biography:

Abstract:

It has been well known that solid cancer nests are acidified and immune cells infiltrate into such acidic cancer nests. However, immune cell functions under acidic conditions have not been focused. Our group has investigated the TCR signaling under acidic conditions with Jurkat T cells and human peripheral primary T cells. In Jurkat T cells, the phosphorylation of CD3 and ZAP-70 was induced by the CD3 stimulation at pH 6.3 as well as pH 7.6. Calcium ions were mobilized by the CD3 stimulation at pH 7.6 and the mobilization was strengthened by the co-stimulation with CD28. In contrast to alkaline pH, no calcium ion mobilization was induced by the CD3 stimulation or co-stimulation of CD3 and CD28 at pH 6.3. Neither the stimulation of CD3 nor the co-stimulation of CD3 and CD28 induced the expression of interleukins at pH 6.3. The same results were obtained in human peripheral primary T cells. These results suggest that the downstream pathway of the TCR-signaling does not work in T cells infiltrated into acidic cancer nests. This may be a reason for attenuation of immune cell functions in cancer nests.

 

  • Cancer Biology

Session Introduction

Rasha Khairy

Faculty of Medicine, Cairo University

Title: Expression of Podoplanin in Laryngeal Squamous Cell Carcinoma and Dysplasia
Speaker
Biography:

Abstract:

 

Introduction: In human cancers, podoplanin expression and its correlation with tumour invasive potential raise its possible role as a diagnostic and prognostic marker for cancer.Aim:To investigate the immunohistochemical expression of podoplanin in laryngeal Squamous Cell Carcinoma (SCC) and dysplasia.Materials and Methods:This study included a total of 60 archived, formalin fixed, paraffin embedded tissue blocks of 40 cases of laryngeal SCC and 20 cases of dysplastic lesions. The samples were immunohistochemically analysed for podoplanin expression.Results:Podoplanin expression was significantly higher in laryngeal SCC (90%) than laryngeal dysplastic lesions (55%) (p-value=0.002). The expression of podoplanin was significantly increased with the higher grades of dysplasia (p-value=0.016). A significant positive correlation was detected between podoplanin expression in laryngeal SCC and depth of tumour invasion (p-value=0.035), and stage (p-value=0.026).Conclusion:The high expression of podoplanin in laryngeal SCC and its significant correlation with poor prognostic parameters recommends podoplanin as a prognostic marker in laryngeal SCC. In addition, increased podoplanin expression with higher grades of dysplasia, supports its role in malignant transformation and allows us to recommend its evaluation in premalignant lesions.KeywordsImmunohistochemistry, Invasive potential, Laryngeal carcinoma, Malignant transformation

Speaker
Biography:

Abstract:

To be updated

Speaker
Biography:

Abstract:

Objectives: Oral Squamous Cell Carcinoma (OSCC) is a very invasive multistage process malignancy. It affects the stratified squamous epithelial cells of the oral mucosa and associated with high death rates worldwide. E-cadherin protein is an important marker of epithelial tissue and it is one of the key regulators of tissue integrity and polarity. The effect of E-cadherin protein down regulation with tumour progression is well known to be associated with poor prognosis. However, the way that this protein affects cell transcripts is still not well understood.

Methods: Mouse Embryonic Stem cells (mESCs) were used as a model for epithelial tissue alongside E-cadherin knock out mESCs (Ecad-/-mESCs). Microarray analysis and Methylation sequencing were done for both cell lines. The results were assessed using Venn 2.1.1 bioinformatic, Bismark v0.17,GRAETAnnotation web tool mouse UCSC mm10 genome browser. The shared data between Microarray and Methylation sequencing were tested on OSCC tissue sections using immunofluorescence staining.

Results: The Microarray has shown several thousand transcripts alterations which govern a number of biological processes. Some of these transcripts were upregulated while others were downregulated. The E-cadherin inhibition has shown bias toward hypermethylation of 10861annotated regions ± fromTranscription Start Site (TSS) compared to hypomethylation (972 annotated regions ± TSS). About 1417 of hypermethylated regions were in CpG islands. Venn bioinformatics has identified 10% of data shared between microarray downregulated transcripts and hypermethylated genes. On the other hand, microarray upregulated genes and hypomethylated genes have shown 4% of shared data. The immunofluorescence evaluation of some shared genes on OSCC tissue sections has shown significant effect of E-cadherin inhibition on their expression.

Conclusion: The inhibition of E-cadherin protein has a role on genes expression and methylation in mESC compared to Ecad-/-mESC, with bias toward increase genes methylation. The study highlighted some genes that were regulated by E-cadherin inhibition during Oral Squamous Cell Carcinoma formation.

  • Pharmacology
Speaker
Biography:

Hussein Albarazanchi born in Iraq, 1977, has M.Sc. cancer pharmacology from university of Bradford-institute of cancer therapeutics, and also has Bachelor degree in veterinary medicine and surgery from college of veterinary medicine-university of sulaimani-Kurdistan of Iraq. Currently he is working as a researcher in Kurdistan institute for strategic studies and scientific research-cancer research Dept., Kurdistan of Iraq; and as a lecturer of anticancer drugs in college of pharmacy university of sulaimani.

Abstract:

Tamoxifen is one of the selective estrogen receptor modulators (SERM) with tissue-specific activities for the treatment and prevention of estrogen receptor positive breast cancer. Tamoxifen acts as an anti-estrogen (inhibiting agent) in the mammary tissue, but as an estrogen (stimulating agent) in cholesterol metabolism, bone density, and cell proliferation in the endometrium.

Mechanism of action:

Tamoxifen is a nonsteroidal agent that binds to estrogen receptors (ER), inducing a conformational change in the receptor. This results in a blockage or change in the expression of estrogen dependent genes. The prolonged binding of tamoxifen to the nuclear chromatin of these results in reduced DNA polymerase activity, impaired thymidine utilization, blockade of estradiol uptake, and decreased estrogen response. It is likely that tamoxifen interacts with other coactivators or corepressors in the tissue and binds with different estrogen receptors, ER-alpha or ER-beta, producing both estrogenic and antiestrogenic effects.