Advances in breast cancer treatment and prevention: preclinical studies on aromatase inhibitors and new selective estrogen receptor modulators (SERMs).

Intensive basic and clinical research over the past 20 years has yielded crucial molecular understanding into how estrogen and the estrogen receptor act to regulate breast cancer and has led to the development of more effective, less toxic, and safer hormonal therapy agents for breast cancer management and prevention. Selective potent aromatase inhibitors are now challenging the hitherto gold standard of hormonal therapy, the selective estrogen-receptor modulator tamoxifen. Furthermore, new selective estrogen-receptor modulators such as arzoxifene, currently under clinical development, offer the possibility of selecting one with a more ideal pharmacological profile for treatment and prevention of breast cancer. Two recent studies in preclinical model systems that evaluate mechanisms of action of these new drugs and suggestions about their optimal clinical use are discussed

Expression Of Estrogen Receptor (Er), Progesterone Receptor (Pr), And Human Epi- Dermal Growth Factor Receptor-2 (Her-2) In Growth And Metastases Of Breast Cancer

Introduction: Breast cancer is a multifactorial disease as a result of interaction between ge- netic and environmental factors such as hormonal, infection, chemical material, and radiation. Until now, it took as the most occurred of cancer in women, which have the highest mortality in the world. However, its cause still unknown. According to epidemiologic and clinical - laboratory studies, it was found that there are many risk factors which have important roles in female breast cancer like menarche, menopause, endogenous and exogenous hormones, family his- tory (genetics), parity, lactation, obesity, physical activity, diet, alcohol, smoking, environmental factors and history of biopsy and breast examination. The aims of this study to evaluate and compare the clinicopathological features in the four breast cancer subtypes defined by immu- nohistochemistry expression of ER, PR, and HER-2: ER/PR+, HER-2+ (Luminal B); ER/ PR+,HER-2- (Luminal A); ER/PR-, HER-2+ (HER-2 type) and ER-/PR-, HER-2- (Triple nega- tive) type. Methods: This study was a retrospective study of 89 invasive breast cancer. Clini- cal and pathologic features of the four subtypes were compared. Results: ER/PR+, HER2+; ER/PR+, HER2-; ER/PR-, HER2+; and ER/PR-,HER2- types were 10 (11.2%), 35 (39.3%), 27 (30.3%), and 17 (19.1%) samples. Subjects with ER/PR-, HER2- where are likely to be younger (p<0.001). In tumor subtypes with HER2+, the number of subjects with poorly differentiated was larger than the total number of well and moderate differentiated (p < 0.001). There was no significant difference of metastatic to lymph node status in all subtypes. Conclusion: Subtype luminal A of breast cancer have a high number than other subtypes. There was a correlation between overexpression of HER-2 with poorly differentiated of breast cancer but not with a metastatic capability of tumor cells to lymph nodes

The significance of GATA3 expression in breast cancer: a 10-year follow-up study.

GATA3 is a transcription factor closely associated with estrogen receptor alpha in breast carcinoma, with a potential prognostic utility. This study investigated the immunohistochemical expression of GATA3 in estrogen receptor alpha-positive and estrogen receptor alpha-negative breast carcinomas. One hundred sixty-six cases of invasive breast carcinomas with 10-year follow-up information were analyzed. Positive GATA3 and estrogen receptor alpha cases were defined as greater than 20% of cells staining. Time to cancer recurrence and time to death were analyzed with survival methods. Of 166 patients, 40 were estrogen receptor alpha negative and 121 estrogen receptor alpha positive. Thirty-eight (23%) recurrences and 51 (31%) deaths were observed. In final multivariable analyses, GATA3-positive tumors had about two thirds the recurrence risk of GATA3-negative tumors (hazard ratio = 0.65, P = .395) and comparable mortality risk (hazard ratio = 0.86, P = .730). In prespecified subgroup analyses, the protective effect of GATA3 expression was most pronounced among estrogen receptor alpha-positive patients who received tamoxifen (hazard ratio = 0.57 for recurrence and 0.68 for death). We found no statistically significant differences in recurrence or survival rates between GATA3-positive and GATA3-negative tumors. However, there was a suggestion of a modest-to-strong protective effect of GATA3 expression among estrogen receptor alpha-positive patients receiving hormone therapy

Selective Association of Peroxiredoxin 1 with Genomic DNA and COX-2 Upstream Promoter Elements in Estrogen Receptor Negative Breast Cancer Cells

PRDX1 was identified as a protein preferentially crosslinked to DNA in estrogen receptor negative but not in estrogen receptor positive breast cancer cells. In estrogen receptor negative cells, PRDX1 is phosphorylated, binds to NF-κB, and is recruited to COX-2 upstream promoter elements

Uji In Silico Senyawa 2,6-dihidroksiantraquinon sebagai Ligan pada Reseptor Estrogen Alfa

Previous studies has shown that estrogen receptor alpha that binds to estrogen may increase cancer cell proliferation, thus estrogen receptor alpha can be targeted to cure breast cancer. The aim of this in silico study is to test whether phytoestrogen 2,6-dihydroxyanthraquinone is a ligand of estrogen receptor alpha. Setiawati et al. (2014) has established a valid protocol for Structure Based Virtual Screening using molecular docking software PLANTS 1.2. This protocol is used to test 2,6-dihydroxyanthraquinone as ligand for estrogen receptor alpha. Output from the protocol is analyzed using a post-docking analysis method developed by Istyastono (2015) in R 3.0.2. Visualization of binding pose is generated with PyMOL 1.2. Results show that 2,6-dihydroxyanthraquinone cannot be identified as a ligand of estrogen receptor alpha. The method used in this study is not suitable to identify 2,6-dihydroxyanthraquinone, which is a marginal active substance, as active ligand. Further study to develop a suitable method to identify marginal active substances as ligands in estrogen receptor alpha is needed

UJI IN SILICO SENYAWA 2,6-DIHIDROKSIANTRAQUINON SEBAGAI LIGAN PADA RESEPTOR ESTROGEN ALFA

Previous studies has shown that estrogen receptor alpha that binds to estrogen may increase cancer cell proliferation, thus estrogen receptor alpha can be targeted to cure breast cancer. The aim of this in silico study is to test whether phytoestrogen 2,6-dihydroxyanthraquinone is a ligand of estrogen receptor alpha. Setiawati et al. (2014) has established a valid protocol for Structure Based Virtual Screening using molecular docking software PLANTS 1.2. This protocol is used to test 2,6-dihydroxyanthraquinone as ligand for estrogen receptor alpha. Output from the protocol is analyzed using a post-docking analysis method developed by Istyastono (2015) in R 3.0.2. Visualization of binding pose is generated with PyMOL 1.2. Results show that 2,6-dihydroxyanthraquinone cannot be identified as a ligand of estrogen receptor alpha. The method used in this study is not suitable to identify 2,6-dihydroxyanthraquinone, which is a marginal active substance, as active ligand. Further study to develop a suitable method to identify marginal active substances as ligands in estrogen receptor alpha is needed

mRNA expression profiles show differential regulatory effects of microRNAs between estrogen receptor-positive and estrogen receptor-negative breast cancer

Most microRNAs have a stronger inhibitory effect in estrogen receptor-negative than in estrogen receptor-positive breast cancer

GPER agonist G-1 decreases adrenocortical carcinoma (ACC) cell growth in vitro and in vivo

We have previously demonstrated that estrogen receptor (ER) alpha (ESR1) increases proliferation of adrenocortical carcinoma (ACC) through both an estrogen-dependent and -independent (induced by IGF-II/IGF1R pathways) manner. Then, the use of tamoxifen, a selective estrogen receptor modulator (SERM), appears effective in reducing ACC growth in vitro and in vivo. However, tamoxifen not only exerts antiestrogenic activity, but also acts as full agonist on the G protein-coupled estrogen receptor (GPER). Aim of this study was to investigate the effect of a non-steroidal GPER agonist G-1 in modulating ACC cell growth. We found that G-1 is able to exert a growth inhibitory effect on H295R cells both in vitro and, as xenograft model, in vivo. Treatment of H295R cells with G-1 induced cell cycle arrest, DNA damage and cell death by the activation of the intrinsic apoptotic mechanism. These events required sustained extracellular regulated kinase (ERK) 1/2 activation. Silencing of GPER by a specific shRNA partially reversed G-1-mediated cell growth inhibition without affecting ERK activation. These data suggest the existence of G-1 activated but GPER-independent effects that remain to be clarified. In conclusion, this study provides a rational to further study G-1 mechanism of action in order to include this drug as a treatment option to the limited therapy of ACC

The Role of GLI-1 in Endocrine Resistant Breast Cancer

Estrogen receptor positive (ER+) and estrogen receptor negative (ER-) are two major types of breast cancer. For women with ER+ positive breast cancer, patients are treated with the antiestrogenic compounds, tamoxifen or faslodex for five years, immediately after surgical resection of tumors. Unfortunately, 30-40% of these patients will develop resistance to endocrine therapy. Our recent study has shown that the Hedgehog (Hhg) signaling pathway plays a significant role in endocrine resistance and that the aberrantly activated transcription factor, GLI-1, is vital to the development of resistance. However, not much is known about the GLI-1 target genes that might contribute to endocrine resistance. Our goal is to determine novel target genes of GLI-1 and determine how these genes promote endocrine therapy resistance.PelotoniaA five-year embargo was granted for this item.Academic Major: Biomedical Scienc

Estrogen Receptor Expression in Pancreatic Adenocarcinoma: Time to Reconsider Evidence

Pancreatic adenocarcinoma remains a chemotherapy-resistant and refractory malignancy with high mortality, unaffected by recent progress in anticancer treatment. Expression of estrogen receptors was detected almost 50 years ago, in both benign and malignant pancreatic cells. However, early preclinical studies in pancreatic cancer led to contradictory findings, and most clinical studies failed to demonstrate an effect with tamoxifen treatment. The identification of a second form of estrogen receptor seems to provide some explanation for these discrepancies. Predominantly expressed in malignant cells and structurally different from what was considered the only estrogen receptor, estrogen receptor β was recognized as a negative prognostic factor and a possible therapeutic target in pancreatic ductal adenocarcinoma. Therefore, findings of research before the identification of estrogen receptor β should be reconsidered, and further studies should be designed to reassess the expression and effect of this specific estrogen receptor type in pancreatic cancer