Celecoxib in breast cancer prevention and therapy.

Breast cancer has a high incidence worldwide. The results of substantial studis reveal that inflammation plays an important role in the initiation, development, and aggressiveness of many malignancies. The use of celecoxib, a novel NSAID, is repetitively associated with the reduced risk of the occurrence and progression of a number of types of cancer, particularly breast cancer. This observation is also substantiated by various meta-analyses. Clinical trials have been implemented on integration treatment of celecoxib and shown encouraging results. Celecoxib could be treated as a potential candidate for antitumor agent. There are, nonetheless, some unaddressed questions concerning the precise mechanism underlying the anticancer effect of celecoxib as well as its activity against different types of cancer. In this review, we discuss different mechanisms of anticancer effect of celecoxib as well as preclinical/clinical results signifying this beneficial effect

Association of Vitamin D3 Level with Breast Cancer Risk and Prognosis in African-American and Hispanic Women.

Background: This study investigated the association of vitamin D3 levels with breast cancer risk and progression in African-Americans and Hispanics. Methods: A total of 237 African-American (Cases = 119, Control = 118) and 423 Hispanic women (Cases = 124, Control = 299) were recruited in the study. Blood samples were collected at the time of breast cancer screening and prior to cancer treatment for 4 weeks on average for the cases. The serum 25-hydroxyvitamin D (25(OH)D3) was measured at a Quest-Diagnostics facility. Results: The results showed that 69.2% of African-Americans and 37.8% of Hispanics had 25(OH)D3 levels below 20 ng/mL. The 25(OH)D3 level below 20 ng/mL was significantly associated with breast cancer in both African-Americans (OR = 2.5, 95% CI = 1.3-4.8) and Hispanics (OR = 1.9, 95% CI = 1.1-3.0). However, the predicted probabilities of breast cancer in African-Americans were significantly higher than in Hispanics (p < 0.001). The 25(OH)D3 below 20 ng/mL was significantly associated with triple negative breast cancer (TNBC) in African-Americans (OR = 5.4, p = 0.02, 95% CI = 1.4-15), but not in Hispanics in our cohort of participants. Levels of 25(OH)D3 below 26 ng/mL predicts a decrease in disease-free survival, but it was not an independent predictor. Conclusions: Our data shows an association between 25(OH)D3 levels and the risk of breast cancer. Further studies on the relationship between 25(OH)D3 level and breast cancer risk are warranted

MCP-1 is overexpressed in triple-negative breast cancers and drives cancer invasiveness and metastasis.

BACKGROUND:Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer that lacks ER/PR and HER2 receptors. Hence, there is urgency in developing new or novel therapeutic strategies for treatment of TNBC. Our study shows that the Monocyte Chemoattractant Protein-1 (MCP-1) is a marker associated with TNBC and may play a key role in TNBC disease progression. EXPERIMENTAL DESIGN:ELISA method was used to measure secreted MCP-1, and mRNA levels were determined by Real-time PCR in numerous cancer cell lines, representing various breast cancer subtypes. Cellular invasiveness was determined by Boyden chamber assay. RESULTS:Our data show that MCP-1 is upregulated in TNBC cell lines both transcriptionally as well as in secreted protein levels compared to ER-positive luminal cell line, MCF-7. Breast cancer patients, with Basal or Claudin-low subtypes, also showed high expression of MCP-1. MCP-1 treatment induced cell invasion in various breast cancer cell types, without affecting cell proliferation. Small molecule antagonists against Chemokine Receptor 2 (CCR2), cognate receptor for MCP-1 as well as the MAP kinase pathway inhibitor U0126 negatively affected MCP-1 induced MCF-7 cell invasion. This suggests that MCP-1-CCR2 axis may regulate invasiveness via the MAP Kinase pathway. Knocking down MCP-1 decreased cell invasion in TNBC cell line BT-549, along with downregulation of key epithelial to mesenchymal transition markers, N-cadherin and Vimentin. CONCLUSION:Our study suggests that MCP-1 mediated pathways could be potential therapeutic targets for the treatment of TNBC, and could reduce cancer health disparities

IGF-1 regulates Cyr61 induced breast cancer cell proliferation and invasion.

BackgroundStudies from our laboratory and others have shown that cysteine-rich 61 (Cyr61) may be involved in tumor proliferation and invasion. In earlier studies, we demonstrated increased insulin-like growth factor-I (IGF-1) is associated with breast tumor formation and poor clinical outcomes. In our current study we have investigated IGF-1 regulation of Cyr61 and whether targeting IGF-1 could inhibit Cyr61 induced tumor growth and proliferation.MethodsSeveral ATCC derived normal and breast cancer cell lines were used in this study: MDA-MB231, BT474, MCF-7, and SKBR3. We also tested cells stably transfected in our laboratory with active Akt1 (pAkt; SKBR3/AA and MCF-7/AA) and dominant negative Akt1 (SKBR3/DN and MCF-7/DN). In addition, we used MCF-7 cells transfected with full length Cyr61 (CYA). Monolayer cultures treated with IGF-1 were analyzed for Cyr61 expression by RT-PCR and immunohistochemical staining. Migration assays and MTT based proliferation assays were used to determine invasive characteristics in response to IGF-1/Cyr61 activation.ResultsCells with activated Akt have increased levels of Cyr61. Conversely, cells with inactive Akt have decreased levels of Cyr61. IGF-1 treatment increased Cyr61 expression significantly and cells with high level of Cyr61 demonstrate increased invasiveness and proliferation. Cyr61 overexpression and activation led to decrease in E-cadherin and decrease in FOXO1. Inhibition of the PI3K and MAPK pathways resulted in significant decrease in invasiveness and proliferation, most notably in the PI3K pathway inhibited cells.ConclusionThe findings of this study show that IGF-1 upregulates Cyr61 primarily through activation of the Akt-PI3K pathway. IGF-1 induced MAPK plays a partial role. Increase in Cyr61 leads to increase in breast cancer cell growth and invasion. Hence, targeting Cyr61 and associated pathways may offer an opportunity to inhibit IGF-1 mediated Cyr61 induced breast cancer growth and invasion

Transcriptomic and ChIP-sequence interrogation of EGFR signaling in HER2+ breast cancer cells reveals a dynamic chromatin landscape and S100 genes as targets.

BACKGROUND:The Human Epidermal Growth Factor Receptor (EGFR/HER1) can be activated by several ligands including Transforming Growth Factor alpha (TGF-α) and Epidermal Growth Factor (EGF). Following ligand binding, EGFR heterodimerizes with other HER family members, such as HER2 (human epidermal growth factor receptor-2). Previously, we showed that the EGFR is upregulated in trastuzumab resistant HER2 positive (HER2+) breast cancer cells. This study is aimed to determine the downstream effects on transcription following EGFR upregulation in HER2+ breast cancer cells. METHODS:RNA-sequence and ChIP-sequence for H3K18ac and H3K27ac (Histone H3 lysine K18 and K27 acetylation) were conducted following an Epidermal Growth Factor (EGF) treatment time course in HER2+ breast cancer cells, SKBR3. The levels of several proteins of interest were confirmed by western blot analysis. The cellular localization of proteins of interest was examined using biochemically fractionated lysates followed by western blot analysis. RESULTS:Over the course of 24 h, EGFR stimulation resulted in the modulation of over 4000 transcripts. Moreover, our data demonstrates that EGFR/HER2 signaling regulates the epigenome, with global H3K18ac and H3K27ac oscillating as a function of time following EGF treatment. RNA-sequence data demonstrates the activation of immediate early genes (IEGs) and delayed early genes (DEGs) within 1 h of EGF treatment. More importantly, we have identified members of the S100 (S100 Calcium Binding Protein) gene family as likely direct targets of EGFR signaling as H3K18ac, H3K27ac and pol2 (RNA polymerase II) increase near the transcription start sites of some of these genes. CONCLUSIONS:Our data suggests that S100 proteins, which act as Ca2+ sensors, could play a role in EGF induced tumor cell growth and metastasis, contribute to trastuzumab resistance and cell migration and that they are likely drug targets in HER2+ breast cancer

Vitamin D receptor gene polymorphisms and prognosis of breast cancer among African-American and Hispanic women.

BackgroundVitamin D plays a role in cancer development and acts through the vitamin D receptor (VDR). Although African-Americans have the lowest levels of serum vitamin D, there is a dearth of information on VDR gene polymorphisms and breast cancer among African-Americans and Hispanics. This study examines whether VDR gene polymorphisms are associated with breast cancer in these cohorts.MethodsBlood was collected from 232 breast cancer patients (Cases) and 349 non-cancer subjects (Controls). Genotyping for four polymorphic variants of VDR (FokI, BsmI, TaqI and ApaI) was performed using the PCR-RFLP method.ResultsAn increased association of the VDR-Fok1 f allele with breast cancer was observed in African-Americans (OR = 1.9, p = 0.07). Furthermore, the FbTA, FbtA and fbtA haplotypes were associated with breast cancer among African-Americans (p<0.05). Latinas were more likely to have the VDR-ApaI alleles (Aa or aa) (p = 0.008). The VDR-ApaI aa genotype was significantly associated with poorly-differentiated breast tumors (p = 0.04) in combined Cases. Kaplan-Meier survival analysis showed decreased 5-year disease-free-survival (DFS) in breast cancer patients who had the VDR-Fok1 FF genotype (p<0.05). The Cox regression with multivariate analysis revealed the independent predictor value of the VDR-FokI polymorphism for DFS. The other three variants of VDR (BsmI, TaqI and ApaI) were not associated with disease outcome.ConclusionsVDR haplotypes are associated with breast cancer in African-Americans, but not in Hispanic/Latinas. The VDR-FokI FF genotype is linked with poor prognosis in African-American women with breast cancer

Lactate, a Neglected Factor for Diabetes and Cancer Interaction

Increasing body of evidence suggests that there exists a connection between diabetes and cancer. Nevertheless, to date, the potential reasons for this association are still poorly understood and currently there is no clinical evidence available to direct the proper management of patients presenting with these two diseases concomitantly. Both cancer and diabetes have been associated with abnormal lactate metabolism and high level of lactate production is the key biological property of these diseases. Conversely, high lactate contribute to a higher insulin resistant status and a more malignant phenotype of cancer cells, promoting diabetes and cancer development and progression. In view of associations between diabetes and cancers, the role of high lactate production in diabetes and cancer interaction should not be neglected. Here, we review the available evidence of lactate's role in different biological characteristics of diabetes and cancer and interactive relationship between them. Understanding the molecular mechanisms behind metabolic remodeling of diabetes- and cancer-related signaling would endow novel preventive and therapeutic approaches for diabetes and cancer treatment