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1.
Int J Cancer ; 2020 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-32949149

RESUMO

We examined the association between established risk factors for breast cancer and microcalcification clusters and their asymmetry. A cohort study of 53 273 Swedish women aged 30 to 80 years, with comprehensive information on breast cancer risk factors and mammograms, was conducted. Total number of microcalcification clusters and the average mammographic density area were measured using a Computer Aided Detection system and the STRATUS method, respectively. A polygenic risk score for breast cancer, including 313 single nucleotide polymorphisms, was calculated for those women genotyped (N = 7387). Odds ratios (ORs) and 95% confidence intervals (CIs), with adjustment for potential confounders, were estimated. Age was strongly associated with microcalcification clusters. Both high mammographic density (>40 cm2 ), and high polygenic risk score (80-100 percentile) were associated with microcalcification clusters, OR = 2.08 (95% CI = 1.93-2.25) and OR = 1.22 (95% CI = 1.06-1.48), respectively. Among reproductive risk factors, life-time breastfeeding duration >1 year was associated with microcalcification clusters OR = 1.22 (95% CI = 1.03-1.46). The association was confined to postmenopausal women. Among lifestyle risk factors, women with a body mass index ≥30 kg/m2 had the lowest risk of microcalcification clusters OR = 0.79 (95% CI = 0.73-0.85) and the association was stronger among premenopausal women. Our results suggest that age, mammographic density, genetic predictors of breast cancer, having more than two children, longer duration of breast-feeding are significantly associated with increased risk of microcalcification clusters. However, most lifestyle risk factors for breast cancer seem to protect against presence of microcalcification clusters. More research is needed to study biological mechanisms behind microcalcifications formation.

2.
Breast Cancer Res ; 22(1): 95, 2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32847607

RESUMO

BACKGROUND: Mammographic density (MD) is a strong risk factor for breast cancer. We examined how endogenous plasma hormones are associated with average MD area (cm2) and annual MD change (cm2/year). METHODS: This study within the prospective KARMA cohort included analyses of plasma hormones of 1040 women. Hormones from the progestogen (n = 3), androgen (n = 7), oestrogen (n = 2) and corticoid (n = 5) pathways were analysed by ultra-performance supercritical fluid chromatography-tandem mass spectrometry (UPSFC-MS/MS), as well as peptide hormones and proteins (n = 2). MD was measured as a dense area using the STRATUS method (mean over the left and right breasts) and mean annual MD change over time. RESULTS: Greater baseline mean MD was associated with overall higher concentrations of progesterone (average + 1.29 cm2 per doubling of hormone concentration), 17OH-progesterone (+ 1.09 cm2), oesterone sulphate (+ 1.42 cm2), prolactin (+ 2.11 cm2) and SHBG (+ 4.18 cm2), and inversely associated with 11-deoxycortisol (- 1.33 cm2). The association between MD and progesterone was confined to the premenopausal women only. The overall annual MD change was - 0.8 cm2. Hormones from the androgen pathway were statistically significantly associated with MD change. The annual MD change was - 0.96 cm2 and - 1.16 cm2 lesser, for women in the highest quartile concentrations of testosterone and free testosterone, respectively, compared to those with the lowest concentrations. CONCLUSIONS: Our results suggest that, whereas hormones from the progestogen, oestrogen and corticoid pathways drive baseline MD, MD change over time is mainly driven by androgens. This study emphasises the complexity of risk factors for breast cancer and their mechanisms of action.

3.
Cancer Epidemiol Biomarkers Prev ; 29(3): 574-581, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31948996

RESUMO

BACKGROUND: Endogenous hormones and mammographic density are risk factors for breast cancer. Joint analyses of the two may improve the ability to identify high-risk women. METHODS: This study within the KARMA cohort included prediagnostic measures of plasma hormone levels of dehydroepiandrosterone (DHEA), its sulfate (DHEAS), and mammographic density in 629 cases and 1,223 controls, not using menopausal hormones. We evaluated the area under the receiver-operating curve (AUC) for risk of breast cancer by adding DHEA, DHEAS, and mammographic density to the Gail or Tyrer-Cuzick 5-year risk scores or the CAD2Y 2-year risk score. RESULTS: DHEAS and percentage density were independently and positively associated with breast cancer risk (P = 0.007 and P < 0.001, respectively) for postmenopausal, but not premenopausal, women. No significant association was seen for DHEA. In postmenopausal women, those in the highest tertiles of both DHEAS and density were at greatest risk of breast cancer (OR, 3.5; 95% confidence interval, 1.9-6.3) compared with the lowest tertiles. Adding DHEAS significantly improved the AUC for the Gail (+2.1 units, P = 0.008) and Tyrer-Cuzick (+1.3 units, P = 0.007) risk models. Adding DHEAS to the Gail and Tyrer-Cuzick models already including mammographic density further increased the AUC by 1.2 units (P = 0.006) and 0.4 units (P = 0.007), respectively, compared with only including density. CONCLUSIONS: DHEAS and mammographic density are independent risk factors for breast cancer and improve risk discrimination for postmenopausal breast cancer. IMPACT: Combining DHEAS and mammographic density could help identify women at high risk who may benefit from individualized breast cancer screening and/or preventive measures among postmenopausal women.

4.
J Natl Cancer Inst ; 112(4): 391-399, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31298705

RESUMO

BACKGROUND: We examined the association between annual mammographic density change (MDC) and breast cancer (BC) risk, and how annual MDC influences the association between baseline mammographic density (MD) and BC risk. METHODS: We used the Karolinska Mammography Project for Risk Prediction of Breast Cancer cohort of Swedish women (N = 43 810) aged 30-79 years with full access to BC risk factors and mammograms. MD was measured as dense area (cm2) and percent MD using the STRATUS method. We used the contralateral mammogram for women with BC and randomly selected a mammogram from either left or right breast for healthy women. We calculated relative area MDC between repeated examinations. Relative area MDC was categorized as decreased (>10% decrease per year), stable (no change), or increased (>10% increase per year). We used Cox proportional hazards regression to estimate the association of BC with MDC and interaction analysis to investigate how MDC modified the association between baseline MD and BC risk. All tests of statistical significance were two-sided. RESULTS: In all, 563 women were diagnosed with BC. Compared with women with a decreased MD over time, no statistically significant difference in BC risk was seen for women with either stable MD or increasing MD (hazard ratio = 1.01, 95% confidence interval = 0.82 to 1.23, P = .90; and hazard ratio = 0.98, 95% confidence interval = 0.80 to 1.22, P = .90, respectively). Categorizing baseline MD and subsequently adding MDC did not seem to influence the association between baseline MD and BC risk. CONCLUSIONS: Our results suggest that annual MDC does not influence BC risk. Furthermore, MDC does not seem to influence the association between baseline MD and BC risk.


Assuntos
Densidade da Mama , Neoplasias da Mama/patologia , Mama/patologia , Adulto , Idoso , Mama/diagnóstico por imagem , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/epidemiologia , Feminino , Humanos , Mamografia/métodos , Mamografia/estatística & dados numéricos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Suécia/epidemiologia
5.
Nat Commun ; 10(1): 4648, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31641120

RESUMO

Breast cancer (BC) patients diagnosed between two screenings (interval cancers) are more likely than screen-detected patients to carry rare deleterious mutations in cancer genes potentially leading to increased risk for other non-breast cancer (non-BC) tumors. In this study, we include 14,846 women diagnosed with BC of which 1,772 are interval and 13,074 screen-detected. Compared to women with screen-detected cancers, interval breast cancer patients are more likely to have a non-BC tumor before (Odds ratio (OR): 1.43 [1.19-1.70], P = 9.4 x 10-5) and after (OR: 1.28 [1.14-1.44], P = 4.70 x 10-5) breast cancer diagnosis, are more likely to report a family history of non-BC tumors and have a lower genetic risk score based on common variants for non-BC tumors. In conclusion, interval breast cancer is associated with other tumors and common cancer variants are unlikely to be responsible for this association. These findings could have implications for future screening and prevention programs.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Programas de Rastreamento , Neoplasias/epidemiologia , Idoso , Neoplasias da Mama/diagnóstico por imagem , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Humanos , Mamografia , Pessoa de Meia-Idade , Neoplasias/etiologia , Neoplasias/genética , Razão de Chances , Fatores de Risco , Fatores Socioeconômicos , Suécia/epidemiologia
6.
Sci Rep ; 9(1): 12524, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31467304

RESUMO

Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.


Assuntos
Neoplasias da Mama/genética , Proteína do Grupo de Complementação C da Anemia de Fanconi/genética , Deleção de Sequência , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Anemia de Fanconi/genética , Proteína do Grupo de Complementação C da Anemia de Fanconi/metabolismo , Feminino , Predisposição Genética para Doença , Variação Genética , Humanos
7.
JNCI Cancer Spectr ; 3(1): pkz004, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31360892

RESUMO

Background: Mammographic density (MD) is a strong risk factor for breast cancer. We examined how breast cancer risk factors are associated with MD area (cm2) change across age. Methods: We conducted a cohort study of 31 782 Swedish women ages 40-70 years at time of baseline mammogram. Lifestyle and reproductive risk factors were assessed by a web-based questionnaire. MD was measured as dense area using the STRATUS method (mean over the left and right breast). Linear regression analyses with adjustments for age, body mass index (BMI), and menopausal status at baseline were performed to assess the association between breast cancer risk factors and mean baseline MD. To investigate mean MD change across age, linear regression analyses with adjustments for age, BMI, menopausal status, and age at last mammogram were performed. All tests of statistical significance were two-sided. Results: Except for oral contraceptive use, established lifestyle and reproductive risk factors for breast cancer were associated with baseline mean MD. The overall average annual MD change was -1.0 cm2. BMI and physical activity were statistically significantly associated with MD change. Lean women (BMI <20 kg/m2) had a mean MD change of -1.13 cm2 per year (95% confidence interval = -1.25 to -1.02) compared with -0.46 cm2 per year (95% confidence interval = -0.57 to -0.35) for women with BMI 30 or higher. The annual MD change was -0.4 cm2 larger in women who were very physically active compared with less physically active women. Conclusions: Our results indicate that all risk factors for breast cancer, except oral contraceptive use, are associated with baseline MD but that only age, BMI, and physical activity are determinants of MD change.

8.
Breast Cancer Res Treat ; 170(3): 487-497, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29603032

RESUMO

INTRODUCTION: Reproductive history has been associated with breast cancer risk, but more knowledge of the underlying biological mechanisms is needed. Because of limited data on normal breast tissue from healthy women, we examined associations of reproductive history and established breast cancer risk factors with breast tissue composition and markers of hormone receptors and proliferation in a nested study within the Karolinska Mammography project for risk prediction for breast cancer (Karma). MATERIALS AND METHODS: Tissues from 153 women were obtained by ultrasound-guided core needle biopsy as part of the Karma project. Immunohistochemical staining was used to assessed histological composition of epithelial, stromal and adipose tissue, epithelial and stromal oestrogen receptor (ER) and progesterone receptor (PR) status, and Ki-67 proliferation status. An individualised reproductive score including parity, number of pregnancies without birth, number of births, age at first birth, and duration of breastfeeding, was calculated based on self-reported reproductive history at the time of the Karma study entry. All analyses were adjusted for age and BMI. RESULTS: Cumulated reproductive score was associated with increased total epithelial content and greater expression of epithelial ER. Parity was associated with greater epithelial area, increased epithelial-stromal ratio, greater epithelial ER expression and a lower extent of stromal proliferation. Increasing numbers of pregnancies and births were associated with a greater epithelial area in the entire study set, which remained significant among postmenopausal women. Increasing numbers of pregnancies and births were also associated with a greater expression of epithelial ER among postmenopausal women. Longer duration of breastfeeding was associated with greater epithelial area and greater expression of epithelial PR both in the entire study set and among postmenopausal women. Breastfeeding was also positively associated with greater epithelial ER expression among postmenopausal women. Prior use of oral contraceptives was associated with lower epithelial-stromal ratio amongst all participants and among pre- and postmenopausal women separately. CONCLUSION: Reproductive risk factors significantly influence the epithelial tissue compartment and expression of hormone receptors in later life. These changes remain after menopause. This study provides deeper insights of the biological mechanisms by which reproductive history influences epithelial area and expression of hormone receptors, and as a consequence the risk of breast cancer.


Assuntos
Biomarcadores , Glândulas Mamárias Humanas/metabolismo , História Reprodutiva , Adulto , Idoso , Biópsia com Agulha de Grande Calibre , Índice de Massa Corporal , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Biópsia Guiada por Imagem , Imuno-Histoquímica , Glândulas Mamárias Humanas/diagnóstico por imagem , Glândulas Mamárias Humanas/patologia , Mamografia/métodos , Pessoa de Meia-Idade , Receptores Estrogênicos , Receptores de Progesterona , Fatores de Risco
9.
Breast Cancer Res ; 20(1): 14, 2018 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-29444691

RESUMO

BACKGROUND: Mammographic breast density is one of the strongest risk factors for breast cancer, but molecular understanding of how breast density relates to cancer risk is less complete. Studies of proteins in blood plasma, possibly associated with mammographic density, are well-suited as these allow large-scale analyses and might shed light on the association between breast cancer and breast density. METHODS: Plasma samples from 1329 women in the Swedish KARMA project, without prior history of breast cancer, were profiled with antibody suspension bead array (SBA) assays. Two sample sets comprising 729 and 600 women were screened by two different SBAs targeting a total number of 357 proteins. Protein targets were selected through searching the literature, for either being related to breast cancer or for being linked to the extracellular matrix. Association between proteins and absolute area-based breast density (AD) was assessed by quantile regression, adjusting for age and body mass index (BMI). RESULTS: Plasma profiling revealed linear association between 20 proteins and AD, concordant in the two sets of samples (p < 0.05). Plasma levels of seven proteins were positively associated and 13 proteins negatively associated with AD. For eleven of these proteins evidence for gene expression in breast tissue existed. Among these, ABCC11, TNFRSF10D, F11R and ERRF were positively associated with AD, and SHC1, CFLAR, ACOX2, ITGB6, RASSF1, FANCD2 and IRX5 were negatively associated with AD. CONCLUSIONS: Screening proteins in plasma indicates associations between breast density and processes of tissue homeostasis, DNA repair, cancer development and/or progression in breast cancer. Further validation and follow-up studies of the shortlisted protein candidates in independent cohorts will be needed to infer their role in breast density and its progression in premenopausal and postmenopausal women.


Assuntos
Proteínas Sanguíneas/genética , Densidade da Mama/genética , Neoplasias da Mama/sangue , Proteômica , Adolescente , Adulto , Idoso , Índice de Massa Corporal , Mama/diagnóstico por imagem , Mama/patologia , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Progressão da Doença , Feminino , Humanos , Mamografia/métodos , Pessoa de Meia-Idade , Pós-Menopausa , Pré-Menopausa , Fatores de Risco , Adulto Jovem
10.
Int J Epidemiol ; 47(2): 526-536, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29315403

RESUMO

Background: Polygenic risk scores (PRS) for breast cancer can be used to stratify the population into groups at substantially different levels of risk. Combining PRS and environmental risk factors will improve risk prediction; however, integrating PRS into risk prediction models requires evaluation of their joint association with known environmental risk factors. Methods: Analyses were based on data from 20 studies; datasets analysed ranged from 3453 to 23 104 invasive breast cancer cases and similar numbers of controls, depending on the analysed environmental risk factor. We evaluated joint associations of a 77-single nucleotide polymorphism (SNP) PRS with reproductive history, alcohol consumption, menopausal hormone therapy (MHT), height and body mass index (BMI). We tested the null hypothesis of multiplicative joint associations for PRS and each of the environmental factors, and performed global and tail-based goodness-of-fit tests in logistic regression models. The outcomes were breast cancer overall and by estrogen receptor (ER) status. Results: The strongest evidence for a non-multiplicative joint associations with the 77-SNP PRS was for alcohol consumption (P-interaction = 0.009), adult height (P-interaction = 0.025) and current use of combined MHT (P-interaction = 0.038) in ER-positive disease. Risk associations for these factors by percentiles of PRS did not follow a clear dose-response. In addition, global and tail-based goodness of fit tests showed little evidence for departures from a multiplicative risk model, with alcohol consumption showing the strongest evidence for ER-positive disease (P = 0.013 for global and 0.18 for tail-based tests). Conclusions: The combined effects of the 77-SNP PRS and environmental risk factors for breast cancer are generally well described by a multiplicative model. Larger studies are required to confirm possible departures from the multiplicative model for individual risk factors, and assess models specific for ER-negative disease.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Predisposição Genética para Doença , Adulto , Idoso , Estudos de Casos e Controles , Europa (Continente)/epidemiologia , Feminino , Interação Gene-Ambiente , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Medição de Risco , Fatores de Risco
11.
JNCI Cancer Spectr ; 2(4): pky055, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31360875

RESUMO

Background: Circulating plasma prolactin is associated with breast cancer risk and may improve our ability to identify high-risk women. Mammographic density is a strong risk factor for breast cancer, but the association with prolactin is unclear. We studied the association between breast cancer, established breast cancer risk factors and plasma prolactin, and improvement of risk prediction by adding prolactin. Methods: We conducted a nested case-control study including 721 breast cancer patients and 1400 age-matched controls. Plasma prolactin levels were assayed using immunoassay and mammographic density measured by STRATUS. Odds ratios (ORs) were calculated by multivariable adjusted logistic regression, and improvement in the area under the curve for the risk of breast cancer by adding prolactin to established risk models. Statistical tests were two-sided. Results: In multivariable adjusted analyses, prolactin was associated with risk of premenopausal (OR, top vs bottom quintile = 1.9; 1.88 (95% confidence interval [CI] = 1.08 to 3.26) but not with postmenopausal breast cancer. In postmenopausal cases prolactin increased by 10.6% per cBIRADS category (P trend = .03). In combined analyses of prolactin and mammographic density, ORs for women in the highest vs lowest tertile of both was 3.2 (95% CI = 1.3 to 7.7) for premenopausal women and 2.44 (95% CI = 1.44 to 4.14) for postmenopausal women. Adding prolactin to current risk models improved the area under the curve of the Gail model (+2.4 units, P = .02), Tyrer-Cuzick model (+3.8, P = .02), and the CAD2Y model (+1.7, P = .008) in premenopausal women. Conclusion: Circulating plasma prolactin and mammographic density appear independently associated with breast cancer risk among premenopausal women, and prolactin may improve risk prediction by current risk models.

13.
Breast Cancer Res Treat ; 158(2): 253-61, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27349429

RESUMO

Following female sex and age, mammographic density is considered one of the strongest risk factors for breast cancer. Despite the association between mammographic density and breast cancer risk, little is known about the underlying histology and biological basis of breast density. To better understand the mechanisms behind mammographic density we assessed morphology, proliferation and hormone receptor status in relation to mammographic density in breast tissues from healthy women. Tissues were obtained from 2012-2013 by ultrasound-guided core needle biopsy from 160 women as part of the Karma (Karolinska mammography project for risk prediction for breast cancer) project. Mammograms were collected through routine mammography screening and mammographic density was calculated using STRATUS. The histological composition, epithelial and stromal proliferation status and hormone receptor status were assessed through immunohistochemical staining. Higher mammographic density was significantly associated with a greater proportion of stromal and epithelial tissue and a lower proportion of adipose tissue. Epithelial expression levels of Ki-67, oestrogen receptor (ER) and progesterone receptor (PR) were not associated with mammographic density. Epithelial Ki-67 was associated with a greater proportion of epithelial tissue, and epithelial PR was associated with a greater proportion of stromal and a lower proportion of adipose tissue. Epithelial ER was not associated with any tissues. In contrast, expression of ER in the stroma was significantly associated with a greater proportion of stroma, and negatively associated with the amount of adipose tissue. High mammographic density is associated with higher amount of stroma and epithelium and less amount of fat, but is not associated with a change in epithelial proliferation or receptor status. Increased expressions of both epithelial PR and stromal ER are associated with a greater proportion of stroma, suggesting hormonal involvement in regulating breast tissue composition.


Assuntos
Mama/diagnóstico por imagem , Mama/patologia , Mamografia/métodos , Receptores Estrogênicos/metabolismo , Células Estromais/metabolismo , Adulto , Idoso , Biópsia com Agulha de Grande Calibre , Mama/metabolismo , Densidade da Mama , Proliferação de Células , Feminino , Humanos , Pessoa de Meia-Idade , Ultrassonografia Mamária
14.
J Vasc Res ; 53(1-2): 17-26, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27344146

RESUMO

INTRODUCTION: Abdominal aortic aneurysm (AAA) is a complex and deadly vascular disorder. The pathogenesis of AAA includes destruction and phenotypic alterations of the vascular smooth muscle cells (VSMCs) and aortic tissues. PPARγ coactivator-1 alpha (PGC1α) regulates VSMC migration and matrix formation and is a major inducer of mitochondrial biogenesis and function, including oxidative metabolism. METHODS: Protein and gene expression of PGC1α and markers for mitochondria biogenesis and cell type-specificity were analysed in AAA aortas from humans and mice and compared against control aortas. RESULTS: Gene expression of PPARGC1A was decreased in human AAA and angiotensin (Ang) II-induced AAA in mice when compared to control vessels. However, high expression of PGC1α was detected in regions of neovascularisation in the adventitia layer. In contrast, the intima/media layer of AAA vessel exhibited defective mitochondrial biogenesis as indicated by low expression of PPARGC1A, VDAC, ATP synthase and citrate synthase. CONCLUSION: Our results suggest that mitochondrial biogenesis is impaired in AAA in synthetic SMCs in the media, with the exception of newly formed supporting vessels in the adventitia where the mitochondrial markers seem to be intact. To our knowledge, this is the first study investigating PGC1α and mitochondria biogenesis in AAA.


Assuntos
Aneurisma da Aorta Abdominal/metabolismo , Mitocôndrias/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Biogênese de Organelas , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Angiotensina II , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/patologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Citrato (si)-Sintase/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Camundongos Knockout , Mitocôndrias/patologia , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Neovascularização Patológica , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Canais de Ânion Dependentes de Voltagem/metabolismo
15.
Biochem Biophys Res Commun ; 469(4): 1090-6, 2016 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-26721434

RESUMO

An increasing body of evidence is pointing towards mitochondrial regulation of the cell cycle. In a previous study of HER2-positive tumours we could demonstrate a common loss in the gene encoding for the mitochondrial transporter SLC25A43 and also a significant relation between SLC25A43 protein expression and S-phase fraction. Here, we investigated the consequence of suppressed SLC25A43 expression on cell cycle progression and proliferation in breast epithelial cells. In the present study, we suppressed SLC25A43 using siRNA in immortalised non-cancerous breast epithelial MCF10A cells and HER2-positive breast cancer cells BT-474. Viability, apoptosis, cell proliferation rate, cell cycle phase distribution, and nuclear Ki-67 and p21, were assessed by flow cytometry. Cell cycle related gene expressions were analysed using real-time PCR. We found that SLC25A43 knockdown in MCF10A cells significantly inhibited cell cycle progression during G1-to-S transition, thus significantly reducing the proliferation rate and fraction of Ki-67 positive MCF10A cells. In contrast, suppressed SLC25A43 expression in BT-474 cells resulted in a significantly increased proliferation rate together with an enhanced G1-to-S transition. This was reflected by an increased fraction of Ki-67 positive cells and reduced level of nuclear p21. In line with our previous results, we show a role for SLC25A43 as a regulator of cell cycle progression and proliferation through a putative mitochondrial checkpoint. These novel data further strengthen the connection between mitochondrial function and the cell cycle, both in non-malignant and in cancer cells.


Assuntos
Mama/citologia , Mama/metabolismo , Pontos de Checagem do Ciclo Celular/fisiologia , Proteínas de Ciclo Celular/metabolismo , Mitocôndrias/fisiologia , Proteínas Supressoras de Tumor/metabolismo , Linhagem Celular , Proliferação de Células/fisiologia , Humanos
16.
PLoS One ; 9(9): e107109, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25243473

RESUMO

Epithelial ovarian carcinoma (EOC), the major cause of gynaecological cancer death, is a heterogeneous disease classified into five subtypes. Each subtype has distinct clinical characteristics and is associated with different genetic risk factors and molecular events, but all are treated with surgery and platinum/taxane regimes. Tumour progression and chemoresistance is generally associated with major metabolic alterations, notably altered mitochondrial function(s). Here, we report for the first time that the expression of the mitochondrial regulators PGC1α and TFAM varies between EOC subtypes; furthermore, we have identified a profile in clear-cell carcinoma consisting of undetectability of PGC1α/TFAM, and low ERα/Ki-67. By contrast, high-grade serous carcinomas were characterised by a converse state of PGC1α/TFAM, ERα positivity and a high Ki-67 index. Interestingly, loss of PGC1α/TFAM and ERα was found also in a non-clear cell EOC cell line made highly resistant to platinum in vitro. Similar to clear-cell carcinomas, these resistant cells also showed accumulation of glycogen. Altogether, our data provide mechanistic insights into the chemoresistant nature of ovarian clear-cell carcinomas. Furthermore, these findings corroborate the need to take into account the diversity of EOC and to develop subtype specific treatment strategies.


Assuntos
Adenocarcinoma de Células Claras/metabolismo , Biomarcadores Tumorais/metabolismo , Cistadenocarcinoma Seroso/metabolismo , Proteínas de Ligação a DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Mitocondriais/metabolismo , Neoplasias Ovarianas/metabolismo , Fatores de Transcrição/metabolismo , Adenocarcinoma de Células Claras/tratamento farmacológico , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Progressão da Doença , Feminino , Glicogênio/metabolismo , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Prognóstico
17.
Oncol Rep ; 29(4): 1268-74, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23354756

RESUMO

The mitochondria have been identified as key players of apoptosis, cell proliferation and cell cycle regulation. However, the role of mitochondria in breast cancer and treatment failure remains unclear. We have previously shown a common deletion of the gene SLC25A43 in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. This gene is coding for a mitochondrial inner membrane transporter and, to date, little is known about the function of this protein. We have also found that low protein expression of SLC25A43 significantly correlates with a lower S phase fraction in HER2-positive breast cancer. The aim of this study was to investigate whether knockdown (KD) of SLC25A43 could have an effect on the cytotoxicity of different cytostatic drugs using MCF10A, MCF7 and BT-474 cells. Following siRNA-mediated KD of SLC25A43, one non-malignant and two breast cancer cell lines were exposed to the anthracycline epirubicin or the taxane paclitaxel. The HER2-positive breast cancer cells were also exposed to the targeted therapy trastuzumab and dual exposure to trastuzumab and paclitaxel. We found that KD of SLC25A43 resulted in a decreased cytotoxic effect of paclitaxel in the two cancer cell lines (P<0.05). Further analysis of cell cycle phase distribution showed that KD increased the paclitaxel-induced G2/M block in these two cell lines (P<0.05). KD of SLC25A43 also reduced the inhibitory effect of trastuzumab on cell proliferation in the HER2-positive cancer cell line BT-474 (P<0.05), and the drug-induced G0/G1 block (P<0.05). Moreover, SLC25A43 influenced the percentage of Ki-67-positive cells. Our findings demonstrate that the mitochondrial protein SLC25A43 affects drug efficacy and cell cycle regulation following drug exposure in breast cancer cell lines.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Paclitaxel/administração & dosagem , Proteínas Supressoras de Tumor/genética , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Farmacológicos/metabolismo , Neoplasias da Mama/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Técnicas de Silenciamento de Genes , Humanos , Células MCF-7 , Mitocôndrias/genética , Mitocôndrias/metabolismo , Receptor ErbB-2/genética , Trastuzumab , Proteínas Supressoras de Tumor/metabolismo
18.
BMC Cancer ; 12: 350, 2012 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-22883974

RESUMO

BACKGROUND: Overexpression of the human epidermal growth factor receptor (HER) 2 is associated with poor prognosis and shortened survival in breast cancer patients. HER2 is a potent activator of several signaling pathways that support cell survival, proliferation and metabolism. In HER2-positive breast cancer there are most likely unexplored proteins that act directly or indirectly downstream of well established pathways and take part in tumor development and treatment response. METHODS: In order to identify novel copy number variations (CNVs) in HER2-positive breast cancer whole-genome single nucleotide polymorphism (SNP) arrays were used. A PCR-based loss of heterozygosis (LOH) assay was conducted to verify presence of deletion in HER2-positive breast cancer cases but also in HER2 negative breast cancers, cervical cancers and lung cancers. Screening for mutations was performed using single-strand conformation polymorphism (SSCP) followed by PCR sequencing. Protein expression was evaluated with immunohistochemistry (IHC). RESULTS: A common deletion at chromosome Xq24 was found in 80% of the cases. This locus harbors the gene solute carrier (SLC) family 25A member 43 (SLC25A43) encoding for a mitochondrial transport protein. The LOH assay revealed presence of SLC25A43 deletion in HER2-positive (48%), HER2-negative (9%), cervical (42%) and lung (67%) cancers. HER2-positive tumors with negative or low SLC25A43 protein expression had significantly lower S-phase fraction compared to tumors with medium or high expression (P = 0.024). CONCLUSIONS: We have found deletion in the SLC25A43 gene to be a common event in HER2-positive breast cancer as well as in other cancers. In addition, the SLC25A43 protein expression was shown to be related to S-phase fraction in HER2-positive breast cancer. Our results indicate a possible role of SLC25A43 in HER2-positive breast cancer and support the hypothesis of altered mitochondrial function in cancer.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Deleção de Genes , Receptor ErbB-2/metabolismo , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Proliferação de Células , Deleção Cromossômica , Cromossomos Humanos X , Variações do Número de Cópias de DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Perda de Heterozigosidade , Pessoa de Meia-Idade , Proteínas Supressoras de Tumor/metabolismo
19.
PLoS One ; 6(2): e16798, 2011 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-21304817

RESUMO

Human mesenchymal stem cells (hMSC) have the ability to differentiate into osteoblasts, adipocytes and chondrocytes. We have previously shown that hMSC were endowed with a basal level of Hedgehog signaling that decreased after differentiation of these cells. Since hMSC differentiation is associated with growth-arrest we investigated the function of Hh signaling on cell proliferation. Here, we show that inhibition of Hh signaling, using the classical inhibitor cyclopamine, or a siRNA directed against Gli-2, leads to a decrease in hMSC proliferation. This phenomenon is not linked to apoptosis but to a block of the cells in the G0/G1 phases of the cell cycle. At the molecular level, it is associated with an increase in the active form of pRB, and a decrease in cyclin A expression and MAP kinase phosphorylation. Inhibition of Hh signaling is also associated with a decrease in the ability of the cells to form clones. By contrast, inhibition of Hh signaling during hMSC proliferation does not affect their ability to differentiate. This study demonstrates that hMSC are endowed with a basal Hedgehog signaling activity that is necessary for efficient proliferation and clonogenicity of hMSC. This observation unravels an unexpected new function for Hedgehog signaling in the regulation of human mesenchymal stem cells and highlights the critical function of this morphogen in hMSC biology.


Assuntos
Proliferação de Células , Proteínas Hedgehog/antagonistas & inibidores , Células-Tronco Mesenquimais/fisiologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Células Cultivadas , Células Clonais , Ensaio de Unidades Formadoras de Colônias , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Proteínas Hedgehog/metabolismo , Humanos , Fatores de Transcrição Kruppel-Like/antagonistas & inibidores , Fatores de Transcrição Kruppel-Like/genética , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , RNA Interferente Pequeno/farmacologia , Transdução de Sinais/efeitos dos fármacos , Teratogênios/farmacologia , Alcaloides de Veratrum/farmacologia , Proteína Gli2 com Dedos de Zinco
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