Current Breast Cancer Treatment Research Articles

Different propolis samples, phenolic content, and breast cancer cell lines: Variable cytotoxicity ranging from ineffective to potent.

Researchers have started focusing on investigating the anticarcinogenic effects of natural products with the slightest side effects possible, because current breast cancer treatment approaches are unable to achieve absolute success especially on aggressive subtypes. Propolis is among these products with its antimicrobial, antifungal, anti-inflammatory, and anticancer effects. Therefore, seven different samples were collected from different regions (Argentina, China, and Istanbul-Turkey) and applied on nonaggressive breast cancer cell line (BCCL) MCF-7 and aggressive cell lines SK-BR-3, and MDA-MB-231. Initially, the phenolic/flavonoid constituents of the propolis ethanol extracts were investigated by liquid chromatography-mass spectrometry-mass spectrometry (LS-MS/MS) and high-performance liquid chromatography (HPLC) analyses. Then, the anticarcinogenic effects of the propolis samples on MCF-7, SK-BR-3, MDA-MB-231 were evaluated by WST1 analysis and only selected ones on MCF-10A and hPdLF. According to the LS-MS/MS and HPLC analysis, Turkey originated propolis (Turkey3) were found to be richer than the other propolis samples in terms of phenolic/flavonoid compounds. Turkey propolis significantly inhibited cell proliferation in both nonaggressive and aggressive BCCL (P < 0.01). Therefore, Turkey3 propolis was selected for further evaluation using Annexin V-PI apoptosis detection assays. In addition, selected compounds among the propolis contents such as galangin, caffeic acid, apigenin, quercetin, and ferulic acid were applied to the MCF-7 cell line to detect cytotoxic and apoptotic effects. Galangin, caffeic acid, apigenin, and quercetin remarkably induced cell proliferation inhibition at all time intervals, whereas ferulic acid was found non efficient on the MCF-7 cell line. Annexin V-PI assay clarified that all cell proliferation inhibitions were markedly apoptotic. Our findings indicated that the inhibition effect of propolis on breast cancer cell proliferation was in a propolis type-, dose- and time-dependent fashion. Turkey3 propolis showed statistically significant cytotoxic effects on both the nonaggressive and aggressive BCCL. These findings were consistent with the effects of its rich phenolic and flavonoid contents, in terms of variety. © 2018 IUBMB Life, 71(5):619-631, 2019.

Moving Breast Cancer Therapy up a Notch.

Breast cancer is the second most common malignancy, worldwide. Treatment decisions are based on tumor stage, histological subtype, and receptor expression and include combinations of surgery, radiotherapy, and systemic treatment. These, together with earlier diagnosis, have resulted in increased survival. However, initial treatment efficacy cannot be guaranteed upfront, and these treatments may come with (long-term) serious adverse effects, negatively affecting a patient's quality of life. Gene expression-based tests can accurately estimate the risk of recurrence in early stage breast cancers. Disease recurrence correlates with treatment resistance, creating a major need to resensitize tumors to treatment. Notch signaling is frequently deregulated in cancer and is involved in treatment resistance. Preclinical research has already identified many combinatory therapeutic options where Notch involvement enhances the effectiveness of radiotherapy, chemotherapy or targeted therapies for breast cancer. However, the benefit of targeting Notch has remained clinically inconclusive. In this review, we summarize the current knowledge on targeting the Notch pathway to enhance current treatments for breast cancer and to combat treatment resistance. Furthermore, we propose mechanisms to further exploit Notch-based therapeutics in the treatment of breast cancer.

Cirugía mayor ambulatoria del cáncer de mama: factores relacionados con la conversión a hospitalización convencional

IntroductionThe main step in curative treatment for breast cancer is surgery. Its use in an ambulatory setting can contribute towards more efficient healthcare, providing additional benefits for patients. In this study, we analyze the results obtained with this treatment method and identify factors related with conversion to hospitalization. MethodsResults were analyzed from the 206 surgeries performed for breast cancer in 2016, using three different methods: day surgery, overnight ambulatory (23h) and conventional hospitalization. The ambulatory success and conversion rates were calculated for the global sample and stratified, distinguishing between conservative surgery, mastectomy and axillary surgery. A univariate analysis was performed to identify the factors involved in conversion. ResultsFor the global sample, the ambulatory surgery rate was 61.2%, 16.5% conversions and a success rate of 83.4%. For conservative surgery, ambulatory, success and conversion rates were 78.8%, 88.6 and 11.4%, respectively. For mastectomies, the ambulatory rate was 28.6%, with 62.9% success and 37.1% conversions. The 11 axillary surgeries were performed as day surgeries. Factors associated with conversion were mastectomy vs. vs. conservative surgery and the appearance of postoperative complications. ConclusionsAmbulatory surgery for the surgical treatment of breast cancer should be standard care. Optimized results require adequate patient selection and the performance of surgical technique that needs to be as careful and as conservative as possible.

Risk‐based breast cancer follow‐up stratified by age

Although personalization of cancer care is recommended, current follow‐up after the curative treatment of breast cancer is consensus‐based and not differentiated for base‐line risk. Every patient receives annual follow‐up for 5 years without taking into account the individual risk of recurrence. The aim of this study was to introduce personalized follow‐up schemes by stratifying for age. Using data from the Netherlands Cancer Registry of 37 230 patients with early breast cancer between 2003 and 2006, the risk of recurrence was determined for four age groups (<50, 50‐59, 60‐69, >70). Follow‐up was modeled with a discrete‐time partially observable Markov decision process. The decision to test for recurrences was made two times per year. Recurrences could be detected by mammography as well as by self‐detection. For all age groups, it was optimal to have more intensive follow‐up around the peak in recurrence risk in the second year after diagnosis. For the first age group (<50) with the highest risk, a slightly more intensive follow‐up with one extra visit was proposed compared to the current guideline recommendation. The other age groups were recommended less visits: four for ages 50‐59, three for 60‐69, and three for ≥70. With this model for risk‐based follow‐up, clinicians can make informed decisions and focus resources on patients with higher risk, while avoiding unnecessary and potentially harmful follow‐up visits for women with very low risks. The model can easily be extended to take into account more risk factors and provide even more personalized follow‐up schedules.

A survey of current surgical treatment of early stage breast cancer in China.

The purpose of this national survey is to explore the patterns of surgical management for early stage breast cancer patients in China. A paper questionnaire survey was sent to the representatives from 520 hospitals who attended an international symposium in Guangzhou, China, 2014. The questionnaire included demographic information, initials and most preferred approaches for breast cancer surgery. The results were presented descriptively. The response rate was 42.5%. Only 7% of hospitals with >50% rate of breast conserving surgery (BCS). Intraoperative frozen sections and additional cavity margins assessment were used at 88% and 30.9% of hospitals, respectively. For invasive carcinoma, 15% of participants defined an adequate margin as no tumor cells on the ink. Sentinel lymph node biopsy (SLNB) was routinely performed in 93.2% of hospitals. Only 16.6% of hospitals would embrace the conclusions of the American College of Surgeons Oncology Group (ACOSOG) Z0011 study and omit axillary lymph node dissection (ALND) for patients who fit the Z0011 criteria. The current patterns for the management of breast cancer patients are still lagging behind. Chinese doctors need to catch up with the updated results of the cutting-edge clinical studies and multiple measures are in need to improve this situation.

Breast cancer treatment and its effects on aging.

Breast cancer is the most common cancer of women in the United States. It is also proving to be one of the most treatable. Early detection, surgical intervention, therapeutic radiation, cytotoxic chemotherapies and molecularly targeted agents are transforming the lives of patients with breast cancer, markedly improving their survival. Although current breast cancer treatments are largely successful in producing cancer remission and extending lifespan, there is concern that these treatments may have long lasting detrimental effects on cancer survivors, in part, through their impact on non-tumor cells. Presently, the impact of breast cancer treatment on normal cells, its impact on cellular function and its effect on the overall function of the individual are incompletely understood. In particular, it is unclear whether breast cancer and/or its treatments are associated with an accelerated aging phenotype. In this review, we consider breast cancer survivorship from the perspective of accelerated aging, and discuss the evidence suggesting that women treated for breast cancer may suffer from an increased rate of physical and cognitive decline that likely corresponds with underlying vulnerabilities of genome instability, epigenetic changes, and cellular senescence.

Cardio-oncology: protecting the heart from curative breast cancer treatment

Patients with breast cancer have higher rates of cardiovascular disease than age-matched controls. Anthracyclines and trastuzumab increase the risk of heart failure (HF) and radiation increases the risk of ischemic heart disease, valvular disease and HF. Older age, low normal ejection fraction, history of coronary artery disease (CAD), cardiac risk factors, higher cumulative anthracycline exposure, combination anthracycline and trastuzumab and/or radiation all increase the risk of cardiac events post treatment. Clinical prediction models (CPMs) and/or genetic testing may be useful in guiding treatment decisions but further external validation is necessary. Screening for asymptomatic cardiotoxicity using echocardiography after completion of therapy is reasonable in patients receiving anthracyclines and/or radiation, especially in those with traditional cardiac risk factors such as hypertension, diabetes, hyperlipidemia, and obesity or with low normal baseline left ventricular ejection fraction (LVEF). Elevated cardiac troponins during anthracycline therapy and early reductions in myocardial deformation may predict subsequent reductions in LVEF but further research is needed to demonstrate clinical benefit to routine screening and early treatment. Neurohormonal antagonist therapy with ACEi/ARBs and beta-blockers are indicated in patients with reduced ejection fraction and ongoing research will clarify the role for neurohormonal antagonists and statins for the prevention of breast cancer therapy cardiotoxicity. Patients treated for breast cancer should be educated on the evidence for optimal lifestyle behaviors such as not smoking, regular exercise, healthy diet and maintaining a healthy weight in reducing the risk of cardiovascular disease. Traditional cardiac risk factors such as hypertension, diabetes and hyperlipidemia should be optimally managed to reduce the risk of cardiovascular events in patients treated for breast cancer.

Pain after curative treatment for breast cancer.

e22200Background: Literature reports that cancer-related pain is experienced by 17-30% of patients with non-metastatic disease and 56-85% with advanced cancer. The characterization of pain followin...

Breast reconstruction after breast conservation therapy for breast cancer.

Conservative breast surgery followed by irradiation, often referred to as Breast conserving therapy (BCT), has replaced modified radical mastectomy for the treatment of early stage invasive breast cancer and ductal carcinoma in situ (DCIS). About 10% to 40% of the patients treated with BCT have poor cosmetic outcome results. Small tumours in large breasts can be successfully treated by lumpectomy and radiotherapy, with good cosmetic outcome. However when the tumour breast ratio is higher, the cosmetic outcome can be very disappointing. A surgical conflict arises between optimal oncologic resection and the desire to spare as much tissue as possible to minimize the risk of deformities. In case of a small defect lipofilling can be performed. This technique transplants fat grafts from a donor site to the defect in the breast. In case of larger defects there is the option of oncoplastic surgery. Oncoplastic techniques combine the optimal oncological resection with an adequate reconstruction for optimal cosmetic outcome. Oncoplastic techniques allow the breast surgeon to perform a tumour resection with adequate margins and the plastic surgeon will reconstruct the defect during the same procedure for optimal cosmetic outcome. The use of oncoplastic techniques to reconstruct defects of partial mastectomies (BCT) can be immediate, delayed or immediate delayed. Current breast cancer treatment leads to long-term surivival. It it there for important not only to survive but also life. Therefore the quality of life and good cosmetic outcome is mandatory after breast cancer treatment. Oncoplastic surgery is based on two techniques: volume displacement and volume replacement. The volume displacement techniques use (dermo)glandular flaps of the breast to fill the resection defect. Volume displacement techniques ideally work when the tumour resection can be incorporated in a breast reduction pattern. A similar technique is used on the contralateral breast to match size and shape. The volume replacement techniques use autologous non-breast tissues to compensate the volume loss after tumour resection. Volume replacement techniques are used when a large resection volume is needed in a small breast. Depending on the location and size of the defect many different flaps can be used for partial breast reconstruction.

Abstract P3-07-05: Potential of breast tumour kinase (Brk) as a therapeutic target: Brk modulates drug responses in breast cancer cell lines

Abstract Background: Breast tumour kinase (Brk/PTK6) is over-expressed in up to 86% of all breast cancers and has shown to be involved in the processes regulating tumour development and progression. A few Brk inhibitors are in development and our studies indicate potential for a Brk inhibitor to be used in combination with current breast cancer therapies. Furthermore the effect of common breast cancer therapies and Brk inhibition on the expression of ptk6 as well as it's alternatively spliced isoform (ALT-PTK6) have not been previously been shown. Using qPCR we have determined gene expression of both genes before and after treatment. Methods: Breast cancer cell lines T47D, GI101, BT474, SKBR3, MDA-MB 231, and MDA-MB 436 were treated with Brk inhibitor, Compound 4f (Mahmoud et al, 2012) and common breast cancer therapies (Taxol, Doxorubicin, Lapatinib and Tamoxifen) at concentrations ranging from 0µM to 10µM. Western blotting was carried out to determine levels of Brk and activation of Brk substrate; STAT3 after treatment with Brk inhibitor. RNA was extracted using Qiagen Mini RNeasy prep kit, cDNA synthesized using Invitrogen Superscript II Reverse Transcriptase and qPCR carried out using primers specific for PTK6 or primers that recognized both transcripts (PTK6 and ALT-PTK6) for total expression. Results: In all cell lines tested there was a moderate reduction in cell proliferation following treatment with the Brk inhibitor (4f). However a greater effect was observed in combination therapy. Triple negative breast cancer cell lines MDA-MB 231 and MDA-MB 436 were treated with Compound 4f and Taxol or Doxorubicin (n=3) resulting in modest but statistically significant reduction in cell numbers. Cell responses to Taxol in both cell lines were significantly greater in the presence of 4f over a range of doses (P between 0.05 and 0.007). Responses to Doxorubicin were also significantly improved in the presence of 4f (P&amp;lt;0.03 for MDA-MB-231 and P=0.03 for MDA-MB-436). Co-treatment of HER2 positive breast cancer cell lines BT474 and Sk-Br-3 with Lapatinib and 4f showed significant increase in responses over a range of doses between 0.31 and 5µM (n=3, P&amp;lt;0.05 for BT474 and P between 0.03 and 0.0004 for Sk-Br-3). In comparison to untreated cells, there was statistically significant reduction in ptk6 and Total gene expression observed at various time points within multiple breast cancer cell lines in response to Compound 4f treatment. Significant differences between untreated and treated cells for T47D cell line were at 8 hours post treatment (p=0.02), 2 and 4 hours post treatment in GI101 cell line (p=0.04 and p=0.02 respectively), 8 and 24 hours post treatment in Sk-Br-3 (p=0.001 and p=0.017 respectively) and 8 hours post treatment in MDA-MB 231 cell lines (p=0.03). Conclusion: Inhibition of Brk led to a decrease in ptk6 gene expression. Expression ratios of ptk6 and the short isoform ALT-PTK6 were determined and a reduction of ptk6 gene correlated with elevation of ALT-PTK6 and vice versa. Inhibition of Brk also indicated an increase in breast cancer cell sensitivity to current breast cancer therapies. Our studies thus indicate potential for inhibition of Brk kinase activity in combination with current breast cancer treatments. Citation Format: Hussain H, Harvey A. Potential of breast tumour kinase (Brk) as a therapeutic target: Brk modulates drug responses in breast cancer cell lines [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-07-05.

Cardiovascular Disease and Breast Cancer: Where These Entities Intersect: A Scientific Statement From the American Heart Association

Cardiovascular disease (CVD) remains the leading cause of mortality in women, yet many people perceive breast cancer to be the number one threat to women's health. CVD and breast cancer have several overlapping risk factors, such as obesity and smoking. Additionally, current breast cancer treatments can have a negative impact on cardiovascular health (eg, left ventricular dysfunction, accelerated CVD), and for women with pre-existing CVD, this might influence cancer treatment decisions by both the patient and the provider. Improvements in early detection and treatment of breast cancer have led to an increasing number of breast cancer survivors who are at risk of long-term cardiac complications from cancer treatments. For older women, CVD poses a greater mortality threat than breast cancer itself. This is the first scientific statement from the American Heart Association on CVD and breast cancer. This document will provide a comprehensive overview of the prevalence of these diseases, shared risk factors, the cardiotoxic effects of therapy, and the prevention and treatment of CVD in breast cancer patients.

CXCR4-targeted Nanoparticles Reduce Cell Viability, Induce Apoptosis and Inhibit SDF-1α Induced BT-549-Luc Cell Migration In Vitro.

CXCR4 possesses a critical role in several intracellular events such as chemotaxis, invasion and adhesion, which are associated with metastasis of cancer cell. In this study, CXCR4 targeted polymeric nanoparticle was developed for delivering cytotoxic drug and blocking the chemokine induced migration of cells expressing CXCR4. A peptide which was a linear form of CXCR4 antagonist (LFC131) was attached to PLGA nanoparticles (LFC131-NPs) and PLGA nanoparticles encapsulating DOX (LFC131-DOX-NPs). The cellular binding and internalization of LFC131-DOX-NPs were investigated. The binding and internalization of LFC131-DOX-NPs were higher and more rapidly compared to unconjugated NPs. LFC131-NPs blocked SDF-1α induced migration of BT-549-Luc cells. MTT assays demonstrated that LFC131-NPs and LFC131-DOX-NPs decreased cell viability in a dose dependent manner in 24, 72 and 120 h incubation. A treatment concept of blocking breast cancer cell migration from interaction with SDF- 1α by using LFC131-NPs and then attacking breast cancer cells with doxorubicin might increase the efficacy of current breast cancer treatment.

Sensitivity of docetaxel-resistant MCF-7 breast cancer cells to microtubule-destabilizing agents including vinca alkaloids and colchicine-site binding agents.

IntroductionOne of the main reasons for disease recurrence in the curative breast cancer treatment setting is the development of drug resistance. Microtubule targeted agents (MTAs) are among the most commonly used drugs for the treatment of breaset cancer and therefore overcoming taxane resistance is of primary clinical importance. Our group has previously demonstrated that the microtubule dynamics of docetaxel-resistant MCF-7TXT cells are insensitivity to docetaxel due to the distinct expression profiles of β-tubulin isotypes in addition to the high expression of p-glycoprotein (ABCB1). In the present investigation we examined whether taxane-resistant breast cancer cells are more sensitive to microtubule destabilizing agents including vinca alkaloids and colchicine-site binding agents (CSBAs) than the non-resistant cells.MethodsTwo isogenic MCF-7 breast cancer cell lines were selected for resistance to docetaxel (MCF-7TXT) and the wild type parental cell line (MCF-7CC) to examine if taxane-resistant breast cancer cells are sensitive to microtubule-destabilizing agents including vinca alkaloids and CSBAs. Cytotoxicity assays, immunoblotting, indirect immunofluorescence and live imaging were used to study drug resistance, apoptosis, mitotic arrest, microtubule formation, and microtubule dynamics.ResultsMCF-7TXT cells were demonstrated to be cross resistant to vinca alkaloids, but were more sensitive to treatment with colchicine compared to parental non-resistant MCF-7CC cells. Cytotoxicity assays indicated that the IC50 of MCF-7TXT cell to vinorelbine and vinblastine was more than 6 and 3 times higher, respectively, than that of MCF-7CC cells. By contrast, the IC50 of MCF-7TXT cell for colchincine was 4 times lower than that of MCF-7CC cells. Indirect immunofluorescence showed that all MTAs induced the disorganization of microtubules and the chromatin morphology and interestingly each with a unique pattern. In terms of microtubule and chromain morphology, MCF-7TXT cells were more resistant to vinorelbine and vinblastine, but more sensitive to colchicine compared to MCF-7CC cells. PARP cleavage assay further demonstrated that all of the MTAs induced apoptosis of the MCF-7 cells. However, again, MCF-7TXT cells were more resistant to vinorelbine and vinblastine, and more sensitive to colchicine compared to MCF-7CC cells. Live imaging demonstrated that the microtubule dynamics of MCF-7TXT cells were less sensitive to vinca alkaloids, and more sensitive to colchicine. MCF-7TXT cells were also noted to be more sensitive to other CSBAs including 2MeOE2, ABT-751 and phosphorylated combretastatin A-4 (CA-4P).ConclusionDocetaxel-resistant MCF-7TXT cells have demonstrated cross-resistance to vinca alkaloids, but appear to be more sensitive to CSBAs (colchicine, 2MeOE2, ABT-751 and CA-4P) compared to non-resistant MCF-7CC cells. Taken together these results suggest that CSBAs should be evaluated further in the treatment of taxane resistant breast cancer.

Nanomedicine applications in the treatment of breast cancer: current state of the art.

Breast cancer is the most common malignant disease in women worldwide, but the current drug therapy is far from optimal as indicated by the high death rate of breast cancer patients. Nanomedicine is a promising alternative for breast cancer treatment. Nanomedicine products such as Doxil® and Abraxane® have already been extensively used for breast cancer adjuvant therapy with favorable clinical outcomes. However, these products were originally designed for generic anticancer purpose and not specifically for breast cancer treatment. With better understanding of the molecular biology of breast cancer, a number of novel promising nanotherapeutic strategies and devices have been developed in recent years. In this review, we will first give an overview of the current breast cancer treatment and the updated status of nanomedicine use in clinical setting, then discuss the latest important trends in designing breast cancer nanomedicine, including passive and active cancer cell targeting, breast cancer stem cell targeting, tumor microenvironment-based nanotherapy and combination nanotherapy of drug-resistant breast cancer. Researchers may get insight from these strategies to design and develop nanomedicine that is more tailored for breast cancer to achieve further improvements in cancer specificity, antitumorigenic effect, antimetastasis effect and drug resistance reversal effect.

Abstract 1756: Genomic reclassification of endometrial carcinoma predicts drug response and facilitates refinement of current management based on PDX-guided efficacy outcomes

Abstract Endometrial cancer (EC) is the most common gynecological malignancy among American women. Steadily increasing numbers of newly diagnosed cases and deaths emphasize the necessity of improving current management strategies. Rather than the commonly known two types of EC based on histological classification, the Cancer Genome Atlas (TCGA) Research Network recently reported a reclassification that categorizes EC into four subtypes based on genomic characterization. Molecular similarities between these subtypes and other cancers, including colorectal, ovarian, and breast cancers, were identified. But to date, no prospective validation has delivered an improved understanding on how to translate these findings to the clinic in the form of treatments adapting genomic guidance. Objectives: To evaluate drug response according to TCGA classification using a panel of twenty-seven established endometrial cancer patient-derived xenografts (EC-PDXs). Methods: Twenty-seven EC-PDXs representing various stages of disease and histological subtypes were orthotopically transplanted and propagated over multiple generations. Upon thorough characterization including histology, metastatic status, and molecular features, EC-PDXs were further categorized into the four TCGA molecular subtypes on the basis of somatic copy number variations (CNV), microsatellite instability (MSI), and POLE mutations. A PDX clinical trial (PCT) was performed to re-evaluate current standard treatments in comparison to therapeutic agents adopted from treatment regimens for other cancer types based on their molecular similarities. Results: EC-PDXs established from patients with recurrent disease exhibited minimal activity to first-line chemotherapeutic drugs, as expected, but remained sensitive to other second-line drugs. None of the tested drugs exhibited sufficient activity in POLE EC-PDXs. MSI EC-PDXs were found to be less sensitive to platinum-based treatment and resistant to 5-FU as reported for MSI colorectal cancer. CNV-high EC-PDXs were more sensitive to drugs adopted from current ovarian and breast cancer treatment regimens. Conclusions: This is the first study that demonstrates the utility of TCGA classification for treatment guidance based on a PCT. Patients with recurrent and persistent disease are in desperate need of new therapeutic options. Our findings open up the possibility to utilize drugs which are currently used in the treatment of other cancers for the treatment of EC based on molecular similarities. In addition, this is the first study that successfully demonstrated the use of molecular classification to enable the prediction of drug response, and thus may facilitate the refinement of current EC management in a more precise and personalized way. Citation Format: Chieh-Hsiang Yang, David K. Gaffney, Theresa L. Werner, Elke A. Jarboe, Jason Gertz, Katherine E. Varley, Matthew Peterson, Margit M. Janat-Amsbury. Genomic reclassification of endometrial carcinoma predicts drug response and facilitates refinement of current management based on PDX-guided efficacy outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1756. doi:10.1158/1538-7445.AM2017-1756

Abstract P6-11-15: Pre-clinical investigation of estrogen receptor β agonists for the treatment of breast cancer

Abstract Breast Cancer is the primary cause of cancer-associated mortality worldwide, and in United States alone, more than 250,000 women are diagnosed every year. Current breast cancer treatment strategies focus on Estrogen Receptor α signaling, given that the majority of cases diagnosed are ERα positive. These treatment strategies include endocrine therapies; such as anti-estrogens or aromatase inhibitors. Although, endocrine therapy has been demonstrated to be successful and effective, therapy resistance commonly arises and results in relapse. While current endocrine therapies focus on ERα signaling, emerging studies highlight the importance of Estrogen Receptor β.Unlike ERα, ERβ has been shown to have tumor-suppressive function in various cancers, including breast cancer. Recent studies have identified, synthesized, and tested the clinical safety of ERβ-selective agonists. The objective of this study was to investigate the utility of using ERβ agonists in the treatment of breast cancer. To investigate the utility of ERβ agonists in the treatment of breast cancer, we used in-vitro and in-vivo pre-clinical models systems. Our results demonstrated that treatment with ERβ agonists, S-Equol and LY500307, was able to inhibit the short-term and long-term growth of both endocrine therapy sensitive and resistant breast cancer cells. Progression through the cell cycle, cell migration and cell invasion was also abrogated upon treatment. In-vivo, our syngeneic tumor mouse model demonstrates a decline in tumor growth rate after treating with a combination of letrozole and ERβ agonist. Gene expression array analysis reveal that treatment with ERβ agonist elicits changes in key signaling molecules involved in cell death and cell cycle pathways. In Letrozole resistant cells, Letrozole treatment had not effect on gene expression, while LY500307 treatment resulted in the modulation of 780 genes. Interestingly, combining Letrozole with LY500307 resulted in the modulation of 966 genes, of which 417 were unique to the combination treatment. Our studies suggest that activation of ERβ signaling is a valuable strategy in the treatment of breast cancer, even in cases which have developed resistance to current endocrine therapies. Citation Format: Samayoa C, Krishnegowda NK, Vadlamudi RK, Tekmal RR. Pre-clinical investigation of estrogen receptor β agonists for the treatment of breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-15.

Paclitaxel-loaded hollow-poly(4-vinylpyridine) nanoparticles enhance drug chemotherapeutic efficacy in lung and breast cancer cell lines

Paclitaxel (PTX), one of the most effective cytotoxins for the treatment of breast and lung cancer, is limited by its severe side effects and low tumor selectivity. In this work, hollow-poly(4-vinylpyridine) (hollow-p4VP) nanoparticles (NPs) have been used for the first time to generate PTX@p4VP NPs, employing a novel technique in which a gold core in the center of the NP is further oxidized to produce the hollow structure into which PTX molecules can be incorporated. The hollow-p4VP NPs exhibit good physicochemical properties and displayed excellent biocompatibility when tested on blood (no hemolysis) and cell cultures (no cytotoxicity). Interestingly, PTX@p4VP NPs significantly increased PTX cytotoxicity in human lung (A-549) and breast (MCF-7) cancer cells with a significant reduction of PTX IC50 (from 5.9 to 3.6 nM in A-549 and from 13.75 to 4.71 nM in MCF-7). In addition, PTX@p4VP caused a decrease in volume of A-549 and MCF-7 multicellular tumor spheroids (MTS), an in vitro system that mimics in vivo tumors, in comparison to free PTX. This increased antitumoral activity is accompanied by efficient cell internalization and increased apoptosis, especially in lung cancer MTS. Our results offer the first evidence that hollow-p4VP NPs can improve the antitumoral activity of PTX. This system can be used as a new nanoplatform to overcome the limitations of current breast and lung cancer treatments.

Multiple molecular targets in breast cancer therapy by betulinic acid.

Breast cancer is the second most common type of cancer in the world, and is by far the most prevalent form of cancer in women. However, the efficacy of current treatments for breast cancer is limited. In addition to the high risk of recurrence, some of these have side effects that significantly reduce the quality of life. Therefore, new avenues of treatment for breast cancer are needed. Betulinic acid (BA), a pipeline anticancer drug, exerts anti-proliferative effects on breast cancer cells is mainly through inhibition of cyclin and topoisomerase expression, leading to cell cycle arrest. It induces apoptosis through mitochondrial pathway and anti-angiogenesis effect by inhibiting the expression of transcription factor nuclear factor kappa B (NF-κB), specificity protein (Sp) transcription factors, and vascular endothelial growth factor (VEGF) signaling. In addition, it exerts anti-metastatic effect by inhibiting the expression of matrix metalloproteases. The specific targets of BA in breast cancer are reported to be the estrogen receptor and various multidrug resistance proteins. Synergistically interactions of BA with other chemotherapeutics are also described in the literature. In this review, we describe the detailed published mechanisms of action of BA, a pentacyclic triterpene with a lupine skeleton, on multiple molecular targets to treat breast cancer. We hope that this review will provide basic information in support of future studies of effects of BA on breast cancer cells.

Axillary contralateral recurrence in breast cancer: case report and literature review

Axillary contralateral lymph nodes recurrence is uncommon after curative breast cancer treatment. When the contralateral axilla is involved in a woman with a breast cancer history, the diagnostic and correct approach are a dilemma. Although it is traditionally considered a distant event, many studies have shown that aberrant lymph drainage is common after previous breast surgery. This might indicate that axillary contralateral lymph nodes recurrence is a regional event. Therefore, its treatment should be with curative rather than palliative intent. The aim of this article was to report the case of a young woman with invasive carcinoma in the left breast and a posterior axillary contralateral recurrence, and to review the literature about this infrequent and controversial issue.

Influence of Hydroalcoholic Vehicle on In Vitro Transport of 4-Hydroxy Tamoxifen Through the Mammary Papilla (Nipple).

Majority of breast cancers originate from epithelial cells in the duct and lobules in the breast. Current systemic treatments for breast cancer are associated with significant systemic side effects, thus warranting localized drug delivery approaches. The aim of this study was to investigate the influence of hydroalcoholic vehicle on topical delivery of 4-hydroxy tamoxifen (4-HT) through the mammary papilla (nipple). The in vitro permeability of 4-HT through porcine mammary papilla was studied using different hydroalcoholic vehicles (0, 33.33, and 66.66% alcohol). Nile red was used as a model lipophilic dye to characterize the drug transport pathway in the mammary papilla. The penetration of 4-HT through the mammary papilla increased with increase in alcohol concentration in the vehicle. The solubility of 4-HT was enhanced by increasing alcohol concentration in the vehicle. On the other hand, the epidermis/vehicle partition coefficient decreased with increase in alcohol concentration. The mammary papilla served as a depot and slowly released 4-HT into the receptor medium. Highest drug penetration was observed with saturated drug solution in 66.66% alcohol, and 4-HT levels were comparable to IC50 value of 4-HT. Results from this study demonstrate the possibility of using mammary papilla as a potential route for direct delivery of 4-HT to the breast.