Dataset Information

Elevation of SIPL1 (SHARPIN) Increases Breast Cancer Risk.

ABSTRACT: SIPL1 (Sharpin) or Sharpin plays a role in tumorigenesis. However, its involvement in breast cancer tumorigenesis remains largely unknown. To investigate this issue, we have systemically analyzed SIPL1 gene amplification and expression data available from Oncomine datasets, which were derived from 17 studies and contained approximately 20,000 genes, 3438 breast cancer cases, and 228 normal individuals. We found a SIPL1 gene amplification in invasive ductal breast cancers compared to normal breast tissues and a significant elevation of SIPL1 mRNA in breast cancers in comparison to non-tumor breast tissues. These results collectively reveal that increases in SIPL1 expression occur during breast cancer tumorigenesis. To further investigate this association, we observed increases in the SIPL1 gene and mRNA in the breast cancer subtypes of estrogen receptor (ER)+, progesterone receptor (PR)+, HER2+, or triple negative. Additionally, a gain of the SIPL1 gene correlated with breast cancer grade and the levels of SIPL1 mRNA associated with both breast cancer stages and grades. Elevation of SIPL1 gene copy and mRNA is linked to a decrease in patient survival, especially for those with PR+, ER+, or HER2- breast cancers. These results are supported by our analysis of SIPL1 protein expression using a tissue microarray containing 224 breast cancer cases, in which higher levels of SIPL1 relate to ER+ and PR+ tumors and AKT activation. Furthermore, we were able to show that progesterone significantly reduced SIPL1 mRNA and protein expression in MCF7 cells. As progesterone enhances breast cancer tumorigenesis in a context dependent manner, inhibition of SIPL1 expression may contribute to progesterone's non-tumorigenic function which might be countered by SIPL1 upregulation. Taken together, we demonstrate a positive correlation of SIPL1 with BC tumorigenesis.

SUBMITTER: De Melo J

PROVIDER: S-EPMC4438068 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Elevation of SIPL1 (SHARPIN) Increases Breast Cancer Risk.

De Melo Jason J Tang Damu D

PloS one 20150519 5

SIPL1 (Sharpin) or Sharpin plays a role in tumorigenesis. However, its involvement in breast cancer tumorigenesis remains largely unknown. To investigate this issue, we have systemically analyzed SIPL1 gene amplification and expression data available from Oncomine datasets, which were derived from 17 studies and contained approximately 20,000 genes, 3438 breast cancer cases, and 228 normal individuals. We found a SIPL1 gene amplification in invasive ductal breast cancers compared to normal breas ...[more]

PMID: 25992689

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Project description:Chemotherapy is a common treatment for breast cancer (BrCa) and can cause chemotherapy-induced peripheral neuropathy (CIPN). CIPN contributes to falls, and is thus a potential risk factor for nontraumatic fractures (NTFx); yet, the effect of CIPN on NTFx risk has not been examined for BrCa survivors. We therefore investigated the association between CIPN and NTFx in BrCa survivors. Data were extracted from Optum's Deidentified Clinformatics® Data Mart Database years 2010-2015 in this retrospective cohort study. Among women, three groups were derived based on BrCa and CIPN status: BrCa+/CIPN+ (primary group of interest), BrCa+/CIPN- (first comparison group), and BrCa-/CIPN- (second comparison group). After propensity score matching the comparison groups to BrCa+/CIPN+ at a ratio of 1:11 (BrCa:control) for demographics, osteoporosis, glucocorticoid medication, comorbidities, and cancer-related variables for BrCa+/CIPN-, 1-year incidence rate (IR) of NTFx was determined for each group. The incident rate ratio (IRR) determined if the IR for NTFx was different for BrCa+/CIPN+ compared to BrCa+/CIPN- and BrCa-/CIPN-. Cox proportional hazards regression models estimated the hazard ratios (HRs) after adjusting for covariates that were unable to be matched for. The crude IR (95% confidence interval [CI]) of NTFx was 4.54 (2.32-6.77) for BrCa+/CIPN+ (n = 359), 2.53 (2.03-3.04) for BrCa+/CIPN- (n = 3949), and 1.76 (1.35-2.18) for BrCa-/CIPN- (n = 3949). The crude IRR of NTFx was significantly elevated for BrCa+/CIPN+ as compared to BrCa+/CIPN- (IRR = 1.80; 95% CI, 1.06-3.05) and BrCa-/CIPN- (IRR = 2.58; 95% CI, 1.50-4.44). The elevated rate of NTFx for BrCa+/CIPN+ remained unchanged after adjusting for aromatase inhibitors compared to BrCa+/CIPN- (HR = 1.79; 95% CI, 1.06-3.04). Female BrCa survivors have an increased 1-year IR of NTFx after the onset of CIPN, suggesting that CIPN is an additive burden on NTFx risk among BrCa survivors. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Project description:Background and objectives: In the evolutionary past, women spent most of their reproductive lives either pregnant or in lactational amenorrhea, and rarely menstruated. The current pattern of frequent menses, and the associated increase in endogenous hormonal exposure, has been implicated in the current breast cancer epidemic. It is not known, however, whether oral contraceptives further increase, or actually decrease, hormonal exposure over one menstrual cycle. Here, we examined variation in hormonal exposure across seven oral contraceptive (OC) formulations, and produced the first quantitative comparison of exogenous versus endogenous hormone exposure. Methodology: Data from 12 studies of serum estradiol (E2) and progesterone (P4) were aggregated to create a composite graph of endogenous hormone levels over one menstrual cycle in European or American women (age 19-40 years). Pharmacokinetic package insert data, also from Western women, were used to calculate exposures for hormones in seven different OC formulations. Endogenous and exogenous hormone levels were compared after adjusting for the relative binding affinity (RBA) of progestin to the progesterone receptor and ethinyl estradiol (EE) to the estrogen receptor. Results: After adjusting for RBA, median ethinyl estradiol exposure across 28 days in the OCs was 11.4 nmol/l, similar to median E2 exposure. One formulation, however, was 40% higher in ethinyl estradiol exposure relative to median endogenous estradiol. Median exposure from progestins in OCs (1496 nmol/l) was 4-fold higher than the median endogenous exposure from P4 (364 nmol/l). Exposure from OC progestins ranged from one sixtieth to 8-fold median endogenous P4 over 28 days. Conclusions and implications: Given that breast cancer risk increases with hormonal exposure, our finding that four widely prescribed formulations more than quadruple progestin exposure relative to endogenous progesterone exposure is cause for concern. As not all formulations produce the same exposures, these findings are pertinent to contraceptive choice. We also identify critical gaps in the provision of relevant data on pharmacokinetics and carcinogenicity by drug manufacturers.

Dataset Information

Elevation of SIPL1 (SHARPIN) Increases Breast Cancer Risk.

Publications

Elevation of SIPL1 (SHARPIN) Increases Breast Cancer Risk.

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