| 1. |
- Brandt, Jasmine, et al.
(author)
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Thyroid-associated genetic polymorphisms in relation to breast cancer risk in the Malmö Diet and Cancer Study
- 2018
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In: International Journal of Cancer. - : Wiley. - 0020-7136. ; 142:7, s. 1309-1321
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Journal article (peer-reviewed)abstract
- Previous studies have suggested that thyroid function is associated with breast cancer risk, which could have an important clinical impact, as one in eight women will develop a thyroid disorder during her lifetime. However, the underlying pathomechanism behind the association is still unknown. We used the Malmö Diet and Cancer Study (a population-based prospective study consisting of 17,035 women) to examine 17 single nucleotide polymorphisms (SNPs) previously related to levels of free thyroxine (free T4) and thyroid peroxidase antibodies (TPO-Ab) as potential genetic risk factors for breast cancer. A baseline examination including free T4 and TPO-Ab levels was conducted at the time of inclusion. Genotyping was performed on 901 breast cancer patients and 3335 controls. Odds ratios (95% confidence intervals) for high free T4, TPO-Ab positivity, and breast cancer were calculated by logistic regression and adjusted for confounders. We identified one free T4-related SNP (rs2235544, D101 gene) that was significantly associated with both free T4 level and breast cancer risk. There was a suggested association between rs11675434 (TPO gene) and TPO-Ab level, and TPO-Ab-related rs11675434 (TPO), rs3094228 (HCP5), rs1033662 (no registered gene), and rs301806 (RERE) were associated with breast cancer risk. There was an indicated interaction between rs6485050 (no registered gene) and free T4 level in regards to breast cancer risk. This is the first study to suggest an association between thyroid-related SNPs and breast cancer risk. All SNPs have a biological plausibility of being associated with breast cancer risk, and may contribute to the genetic predisposition to breast cancer.
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| 2. |
- Danielsson, Frida, et al.
(author)
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Transcriptome profiling of the interconnection of pathways involved in malignant transformation and response to hypoxia
- 2018
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In: Oncotarget. - : Impact Journals LLC. - 1949-2553. ; 9:28, s. 19730-19744
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Journal article (peer-reviewed)abstract
- In tumor tissues, hypoxia is a commonly observed feature resulting from rapidly proliferating cancer cells outgrowing their surrounding vasculature network. Transformed cancer cells are known to exhibit phenotypic alterations, enabling continuous proliferation despite a limited oxygen supply. The four-step isogenic BJ cell model enables studies of defined steps of tumorigenesis: the normal, immortalized, transformed, and metastasizing stages. By transcriptome profiling under atmospheric and moderate hypoxic (3% O2) conditions, we observed that despite being highly similar, the four cell lines of the BJ model responded strikingly different to hypoxia. Besides corroborating many of the known responses to hypoxia, we demonstrate that the transcriptome adaptation to moderate hypoxia resembles the process of malignant transformation. The transformed cells displayed a distinct capability of metabolic switching, reflected in reversed gene expression patterns for several genes involved in oxidative phosphorylation and glycolytic pathways. By profiling the stage-specific responses to hypoxia, we identified ASS1 as a potential prognostic marker in hypoxic tumors. This study demonstrates the usefulness of the BJ cell model for highlighting the interconnection of pathways involved in malignant transformation and hypoxic response.
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| 3. |
- Huss, Linnea, et al.
(author)
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SNPs related to vitamin D and breast cancer risk : A case-control study
- 2018
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In: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 20:1
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Journal article (peer-reviewed)abstract
- Background: It has been suggested that vitamin D might protect from breast cancer, although studies on levels of vitamin D in association with breast cancer have been inconsistent. Genome-wide association studies (GWASs) have identified several single-nucleotide polymorphisms (SNPs) to be associated with vitamin D. The aim of this study was to investigate such vitamin D-SNP associations in relation to subsequent breast cancer risk. A first step included verification of these SNPs as determinants of vitamin D levels. Methods: The Malmö Diet and Cancer Study included 17,035 women in a prospective cohort. Genotyping was performed and was successful in 4058 nonrelated women from this cohort in which 865 were diagnosed with breast cancer. Levels of vitamin D (25-hydroxyvitamin D) were available for 700 of the breast cancer cases and 643 of unaffected control subjects. SNPs previously associated with vitamin D in GWASs were identified. Logistic regression analyses yielding ORs with 95% CIs were performed to investigate selected SNPs in relation to low levels of vitamin D (below median) as well as to the risk of breast cancer. Results: The majority of SNPs previously associated with levels of vitamin D showed a statistically significant association with circulating vitamin D levels. Heterozygotes of one SNP (rs12239582) were found to have a statistically significant association with a low risk of breast cancer (OR 0.82, 95% CI 0.68-0.99), and minor homozygotes of the same SNP were found to have a tendency towards a low risk of being in the group with low vitamin D levels (OR 0.72, 95% CI 0.52-1.00). Results from stratified analyses showed diverse associations with breast cancer risk for a few of the tested SNPs, depending on whether vitamin D level was high or low. Conclusions: SNPs associated with vitamin D may also be associated with the risk of breast cancer. Even if such a risk is small, the allele frequency of the SNP variants is high, and therefore the population attributable risk could be substantial. It is also possible that vitamin D levels may interact with genomic traits with regard to breast cancer risk.
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| 4. |
- Huss, Linnea
(author)
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Vitamin D and Breast Cancer. Studies on Incidence and Survival.
- 2019
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Doctoral thesis (other academic/artistic)abstract
- Previous research has suggested beneficial effects of vitamin D on both breast cancer risk and prognosis. The overall aim of this research project was to investigate associations between vitamin D and breast cancer. The population-based prospective cohort, the Malmö Diet and Cancer Study, recruited 17,034 women in the first half of the 1990s. Studies in in the current thesis are based on blood samples collected at baseline, analyzed for levels of vitamin D, parathyroid hormone (PTH), calcium and later also used for genetic sequencing. Breast tumors that developed in women within the cohort were included in a tissue microarray and analyzed for expression of the vitamin D receptor (VDR). Specific aims were to investigate: I.Serum levels of vitamin D, PTH and calcium in relation to breast cancer survival, i.e. mortality among women diagnosed with breast cancer. II.Vitamin D-related single nucleotide polymorphisms (SNPs) and breast cancer risk.III.Expression of VDR in association with breast cancer mortality.IV.Levels of vitamin D in relation to expression of VDR in subsequent breast tumors. Results and conclusions:I.Compared to intermediate levels of vitamin D, low levels and high levels were associated with a poor survival, i.e. high risk of death related to breast cancer. No association was found between PTH and breast cancer mortality. Relatively high serum calcium levels were associated with relatively low breast cancer mortality.II.SNPs associated with levels of vitamin D did not affect breast cancer risk. One SNP, related to the vitamin D binding protein, was associated with breast cancer risk.III.VDR expression was associated with a favorable breast cancer prognosis.IV.There were indications that vitamin D levels were associated with VDR expression in a subsequent breast tumor.The association between low vitamin D levels and high breast cancer mortality may be mediated through development of a VDR-negative tumor. There was no evidence to suggest an additional beneficiary effect of vitamin D levels higher than intermediate levels.
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| 5. |
- Huss, Linnea, et al.
(author)
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Vitamin D receptor expression in invasive breast tumors and breast cancer survival
- 2019
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In: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 21:1
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Journal article (peer-reviewed)abstract
- Background: Vitamin D has been suggested to prevent and improve the prognosis of several cancers, including breast cancer. We have previously shown a U-shaped association between pre-diagnostic serum levels of vitamin D and risk of breast cancer-related death, with poor survival in patients with the lowest and the highest levels respectively, as compared to the intermediate group. Vitamin D exerts its functions through the vitamin D receptor (VDR), and the aim of the current study was to investigate if the expression of VDR in invasive breast tumors is associated with breast cancer prognosis. Methods: VDR expression was evaluated in a tissue microarray of 718 invasive breast tumors. Covariation between VDR expression and established prognostic factors for breast cancer was analyzed, as well as associations between VDR expression and breast cancer mortality. Results: We found that positive VDR expression in the nuclei and cytoplasm of breast cancer cells was associated with favorable tumor characteristics such as smaller size, lower grade, estrogen receptor positivity and progesterone receptor positivity, and lower expression of Ki67. In addition, both intranuclear and cytoplasmic VDR expression were associated with a low risk of breast cancer mortality, hazard ratios 0.56 (95% CI 0.34-0.91) and 0.59 (0.30-1.16) respectively. Conclusions: This study found that high expression of VDR in invasive breast tumors is associated with favorable prognostic factors and a low risk of breast cancer death. Hence, a high VDR expression is a positive prognostic factor.
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