Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 6 de 6
Filter
1.
Int J Oncol ; 50(1): 49-65, 2017 Jan.
Article in English | MEDLINE | ID: mdl-27959387

ABSTRACT

Alcohol consumption is a risk factor for breast cancer. Little is known regarding the mechanism, although it is assumed that acetaldehyde or estrogen mediated pathways play a role. We previously showed that long-term exposure to 2.5 mM ethanol (blood alcohol ~0.012%) of MCF-12A, a human normal epithelial breast cell line, induced epithelial mesenchymal transition (EMT) and oncogenic transformation. In this study, we investigated in the human breast cancer cell line MCF-7, whether a similar exposure to ethanol at concentrations ranging up to peak blood levels in heavy drinkers would increase malignant progression. Short-term (1-week) incubation to ethanol at as low as 1-5 mM (corresponding to blood alcohol concentration of ~0.0048-0.024%) upregulated the stem cell related proteins Oct4 and Nanog, but they were reduced after exposure at 25 mM. Long-term (4-week) exposure to 25 mM ethanol upregulated the Oct4 and Nanog proteins, as well as the malignancy marker Ceacam6. DNA microarray analysis in cells exposed for 1 week showed upregulated expression of metallothionein genes, particularly MT1X. Long-term exposure upregulated expression of some malignancy related genes (STEAP4, SERPINA3, SAMD9, GDF15, KRT15, ITGB6, TP63, and PGR, as well as the CEACAM, interferon related, and HLA gene families). Some of these findings were validated by RT-PCR. A similar treatment also modulated numerous microRNAs (miRs) including one regulator of Oct4 as well as miRs involved in oncogenesis and/or malignancy, with only a few estrogen-induced miRs. Long-term 25 mM ethanol also induced a 5.6-fold upregulation of anchorage-independent growth, an indicator of malignant-like features. Exposure to acetaldehyde resulted in little or no effect comparable to that of ethanol. The previously shown alcohol induction of oncogenic transformation of normal breast cells is now complemented by the current results suggesting alcohol's potential involvement in malignant progression of breast cancer.


Subject(s)
Breast Neoplasms/pathology , Carcinogenesis/drug effects , Ethanol/toxicity , Metabolic Networks and Pathways/drug effects , Acetaldehyde/metabolism , Breast Neoplasms/chemically induced , Breast Neoplasms/genetics , Cell Proliferation/drug effects , Epithelial-Mesenchymal Transition/drug effects , Estrogens/metabolism , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , MCF-7 Cells , Neoplasm Proteins/biosynthesis
2.
Int J Oncol ; 46(4): 1461-72, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25652255

ABSTRACT

Hormone therapy targeting estrogen receptor α (ERα) is the most effective treatment for breast cancer. However, this treatment eventually fails as the tumor develops resistance. Although reduced expression of ER-α is a known contributing factor to endocrine resistance, the mechanism of ER-α downregulation in endocrine resistance is still not fully understood. The present study shows that Slug has an inverse relationship with ERα in breast and prostate cancer patient samples. Also the inhibition of Slug blocks mammary stem cell activity in primary mammary epithelial cells. We hypothesize that Slug may be a key transcription factor in the regulation of ERα expression. To understand the Slug-ERα signaling pathway, we employed resistant cell line MCF-TAMR (ERα relatively negative) derived from its parental MCF-7 (ERα positive) cell line and assessed changes in cell phenotype, activity and response to therapy. Conversely, we performed knockdown of Slug in the high-Slug expressing cell line MDA-MB-231 and assessed reversal of the mesenchymal phenotype. Microarray analysis showed that Slug is overexpressed in high grade breast and prostate cancer tissues. Additionally, Slug overexpression leads to drug resistance. Furthermore, we demonstrated that Slug binds directly to ERα promoter E-boxes and represses ERα expression. This resulted in decrease in epithelial-to-mesenchymal transition in cancer cells. These findings demonstrate that Slug, by regulation of ERα expression, contributes to tumor progression and could serve as an important target for cancer therapy.


Subject(s)
Breast Neoplasms/pathology , Drug Resistance, Neoplasm , Estrogen Receptor alpha/genetics , Prostatic Neoplasms/pathology , Signal Transduction , Transcription Factors/metabolism , Animals , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Line, Tumor , Disease Progression , Female , Humans , MCF-7 Cells , Male , Mammary Neoplasms, Experimental , Mice , Mice, Nude , Prostatic Neoplasms/metabolism , Snail Family Transcription Factors , Tamoxifen/pharmacology
3.
PLoS One ; 9(7): e103534, 2014.
Article in English | MEDLINE | ID: mdl-25062088

ABSTRACT

BACKGROUND: Studies 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. METHODS: Several 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. RESULTS: Cells 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. CONCLUSION: The 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.


Subject(s)
Breast Neoplasms/metabolism , Cell Proliferation/drug effects , Cysteine-Rich Protein 61/metabolism , Insulin-Like Growth Factor I/pharmacology , 3T3 Cells , Animals , Cadherins/genetics , Cadherins/metabolism , Cell Movement/drug effects , Cysteine-Rich Protein 61/genetics , Forkhead Box Protein O1 , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , MAP Kinase Signaling System , MCF-7 Cells , Mice
4.
Cancer ; 120(9): 1387-93, 2014 May 01.
Article in English | MEDLINE | ID: mdl-24510435

ABSTRACT

BACKGROUND: Vitamin D plays a role in cancer tumorogenesis and acts through the vitamin D receptor (VDR). Although African Americans have the lowest serum vitamin D levels, supplementation has not yielded a significant improvement in cancer. Gene polymorphisms in VDR may play a role. There is a dearth of information on VDR gene polymorphisms and colorectal cancer (CRC) among under-represented ethnic groups. In this study, the authors examined whether VDR gene single nucleotide polymorphisms (SNPs) were associated with CRC in predominately African American and Hispanic study participants. METHODS: Blood samples were collected from 378 participants, including a group of 78 patients with CRC (cases), a group of 230 noncancer participants without polyps (controls without polyps), and a group of 70 noncancer participants with polyps (controls with polyps). The 4 polymorphic SNPs in VDR (FokI, BsmI, TaqI, and ApaI) were assessed using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: There was a significant association of the VDR-FokI FF genotype with CRC cases (odds ratio, 2.9; P= .036) compared with the controls without polyps. The most common VDR-FokI genotype in the overall study population was the FF genotype (46%). However, upon breakdown by ethnicity, the FF genotype was the most common in African American participants (61%), and the Ff genotype was the most common in Hispanic/Latino participants (49%). When the association was assessed in a multivariate model, there was no significant association with any VDR polymorphism and CRC cases (P> .05). The other 3 polymorphic variants of VDR (BsmI, TaqI, and ApaI) were not associated with CRC. CONCLUSIONS: The results from this study suggest that genetic variation of the VDR-FokI SNPs may influence CRC risk, particularly in African American cohorts.


Subject(s)
Black or African American/genetics , Colorectal Neoplasms/genetics , Hispanic or Latino/genetics , Receptors, Calcitriol/genetics , Case-Control Studies , Cohort Studies , Colorectal Neoplasms/blood , Colorectal Neoplasms/ethnology , Colorectal Neoplasms/pathology , Female , Genotype , Haplotypes , Humans , Male , Middle Aged , Multivariate Analysis , Polymerase Chain Reaction , Polymorphism, Restriction Fragment Length , Polymorphism, Single Nucleotide , Retrospective Studies
5.
PLoS One ; 8(3): e57967, 2013.
Article in English | MEDLINE | ID: mdl-23554871

ABSTRACT

BACKGROUND: Vitamin 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. METHODS: Blood 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. RESULTS: An 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. CONCLUSIONS: VDR 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.


Subject(s)
Alleles , Black or African American , Breast Neoplasms/genetics , Breast Neoplasms/mortality , Haplotypes , Hispanic or Latino , Polymorphism, Restriction Fragment Length , Receptors, Calcitriol/genetics , Adult , Breast Neoplasms/blood , Breast Neoplasms/ethnology , Breast Neoplasms/therapy , Case-Control Studies , Disease-Free Survival , Female , Humans , Middle Aged , Receptors, Calcitriol/metabolism , Survival Rate , Vitamin D/blood
6.
Int J Oncol ; 38(6): 1663-73, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21455574

ABSTRACT

Previous studies from our group and others have shown that increased circulatory levels of the ligand insulin-like growth factor 1 (IGF-1) and decreased levels of the predominant IGF-1 binding protein 3 (IGFBP-3) are associated with an increased incidence of breast cancer and poor outcome. Some studies suggest that, in addition to the influence of environmental factors on the levels of IGF-1 and IGFBP-3, alterations in their gene polymorphisms may play a significant role in the risk of cancer. In this study, we investigated the association between gene polymorphisms along the IGF axis and breast cancer, including the IGF-1 (CA) dinucleotide repeat, IGFBP-3 A-202C single nucleotide polymorphism, and the 2-bp deletion and (AGG)n repeat polymorphisms in the IGF type 1 receptor (IGF-IR). A total of 654 subjects, including both African-American and Hispanic/Latino subjects, were screened for various gene polymorphisms. IGF gene polymorphism genotyping was performed by PCR-GeneScan and PCR-RFLP methods. Our results demonstrated a significant association between the non-19/non-19 IGF-1 (CA)n polymorphism and breast cancer (OR = 1.75; 95% CI = 1.07-2.88; P = 0.027). Furthermore, absence of the wild-type-19 allele and alleles <(CA)19 were strongly associated with breast cancer (OR = 1.82; 95% CI = 1.20-2.77; P = 0.005 and OR = 1.70; 95% CI = 1.19-2.43; P = 0.003, respectively). The association of the non-19/non-19 polymorphism with breast cancer was also more significant in premenopausal women (P = 0.04). We did not find any significant association of the IGFBP-3 polymorphism with breast cancer. In the case of IGF-1R polymorphisms, the only significant trend was in the (AGG)5 allele; however, the frequency of this allele was very rare. In summary, our study demonstrated a significant association of IGF-1 polymorphisms and breast cancer. Future studies are necessary to understand the mechanistic value of these polymorphisms in breast cancer risk.


Subject(s)
Black or African American/genetics , Breast Neoplasms/genetics , Hispanic or Latino/genetics , Insulin-Like Growth Factor I/genetics , Polymorphism, Genetic , Adult , Alleles , Female , Genotype , Humans , Insulin-Like Growth Factor Binding Protein 3/genetics , Middle Aged , Receptor, IGF Type 1/genetics , United States/ethnology
SELECTION OF CITATIONS
SEARCH DETAIL
...