| 1. |
- Holm, Johanna, et al.
(författare)
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Assessment of breast cancer risk factors reveals subtype heterogeneity
- 2017
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Ingår i: Cancer Research. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 0008-5472. ; 77:13, s. 3708-3717
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Tidskriftsartikel (refereegranskat)abstract
- Subtype heterogeneity for breast cancer risk factors has been suspected, potentially reflecting etiological differences and implicating risk prediction. Reports are conflicting regarding presence of heterogeneity for many exposures. To examine subtype heterogeneity across known breast cancer risk factors, we conducted a case-control analysis of 2,632 breast cancers and 15,945 controls in Sweden. Molecular subtype was predicted from pathology-record derived immunohistochemistry markers by a classifier trained on PAM50 subtyping. Multinomial logistic regression estimated separate odds ratios for each subtype by the exposures parity, age at first birth, breastfeeding, menarche, HRT use, somatotype at age 18, benign breast disease, mammographic density, polygenic risk score, family history of breast cancer and BRCA mutations. We found clear subtype heterogeneity for genetic factors and breastfeeding. The polygenic risk score was associated with risk of all subtypes except for the basal-like (p heterogeneity < 0.0001). Parous women who never breastfed were at higher risk of basal-like subtype (OR 4.17; 95% CI 1.89 to 9.21) compared to both nulliparous (reference) and breastfeeding women. Breastfeeding was not associated with risk of HER2-overexpressing type, but protective for all other subtypes. The observed heterogeneity in risk of distinct breast cancer subtypes for germline variants supports heterogeneity in etiology and has implications for their use in risk prediction. The increased risk of basal-like subtype among women who never breastfed merits more research into potential causal mechanisms and confounders.
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| 2. |
- Donia, Marco, et al.
(författare)
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Acquired immune resistance follows complete tumor regression without loss of target antigens or IFNγ signaling
- 2017
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Ingår i: Cancer Research. - 0008-5472. ; 77:17, s. 4562-4566
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Tidskriftsartikel (refereegranskat)abstract
- Cancer immunotherapy can result in durable tumor regressions in some patients. However, patients who initially respond often experience tumor progression. Here, we report mechanistic evidence of tumoral immune escape in an exemplary clinical case: a patient with metastatic melanoma who developed disease recurrence following an initial, unequivocal radiologic complete regression after T-cell–based immunotherapy. Functional cytotoxic T-cell responses, including responses to one mutant neoantigen, were amplified effectively with therapy and generated durable immunologic memory. However, these immune responses, including apparently effective surveillance of the tumor mutanome, did not prevent recurrence. Alterations of the MHC class I antigen-processing and presentation machinery (APM) in resistant cancer cells, but not antigen loss or impaired IFNγ signaling, led to impaired recognition by tumor-specific CD8þ T cells. Our results suggest that future immunotherapy combinations should take into account targeting cancer cells with intact and impaired MHC class I–related APM. Loss of target antigens or impaired IFNγ signaling does not appear to be mandatory for tumor relapse after a complete radiologic regression. Personalized studies to uncover mechanisms leading to disease recurrence within each individual patient are warranted.
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| 3. |
- Kurtsdotter, Idha, et al.
(författare)
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SOX5/6/21 prevent oncogene-driven transformation of brain stem cells
- 2017
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 77:18, s. 4985-4997
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Tidskriftsartikel (refereegranskat)abstract
- Molecular mechanisms preventing self-renewing brain stem cells from oncogenic transformation are poorly defined. We show that the expression levels of SOX5, SOX6, and SOX21 (SOX5/6/21) transcription factors increase in stem cells of the subventricular zone (SVZ) upon oncogenic stress, whereas their expression in human glioma decreases during malignant progression. Elevated levels of SOX5/6/21 promoted SVZ cells to exit the cell cycle, whereas genetic ablation of SOX5/6/21 dramatically increased the capacity of these cells to form glioma-like tumors in an oncogene-driven mouse brain tumor model. Loss-of-function experiments revealed that SOX5/6/21 prevent detrimental hyperproliferation of oncogene expressing SVZ cells by facilitating an antiproliferative expression profile. Consistently, restoring high levels of SOX5/6/21 in human primary glioblastoma cells enabled expression of CDK inhibitors and decreased p53 protein turnover, which blocked their tumorigenic capacity through cellular senescence and apoptosis. Altogether, these results provide evidence that SOX5/6/21 play a central role in driving a tumor suppressor response in brain stem cells upon oncogenic insult.
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| 4. |
- Li, Bo, et al.
(författare)
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Therapeutic rationale to target highly expressed CDK7 conferring poor outcomes in triple-negative breast cancer
- 2017
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Ingår i: Cancer Research. - 0008-5472. ; 77:14, s. 3834-3845
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Tidskriftsartikel (refereegranskat)abstract
- Triple-negative breast cancer (TNBC) patients commonly exhibit poor prognosis and high relapse after treatment, but there remains a lack of biomarkers and effective targeted therapies for this disease. Here, we report evidence highlighting the cell-cycle–related kinase CDK7 as a driver and candidate therapeutic target in TNBC. Using publicly available transcriptomic data from a collated set of TNBC patients (n ¼ 383) and the METABRIC TNBC dataset (n ¼ 217), we found CDK7 mRNA levels to be correlated with patient prognosis. High CDK7 protein expression was associated with poor prognosis within the RATHER TNBC cohort (n ¼ 109) and the METABRIC TNBC cohort (n ¼ 203). The highly specific CDK7 kinase inhibitors, BS-181 and THZ1, each downregulated CDK7-mediated phosphorylation of RNA polymerase II, indicative of transcriptional inhibition, with THZ1 exhibiting 500-fold greater potency than BS-181. Mechanistic investigations revealed that the survival of MDA-MB-231 TNBC cells relied heavily on the BCL-2/BCL-XL signaling axes in cells. Accordingly, we found that combining the BCL-2/BCL-XL inhibitors ABT-263/ABT199 with the CDK7 inhibitor THZ1 synergized in producing growth inhibition and apoptosis of human TNBC cells. Collectively, our results highlight elevated CDK7 expression as a candidate biomarker of poor prognosis in TNBC, and they offer a preclinical proof of concept for combining CDK7 and BCL-2/BCL-XL inhibitors as a mechanism-based therapeutic strategy to improve TNBC treatment.
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| 5. |
- Donia, M., et al.
(författare)
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Acquired Immune Resistance Follows Complete Tumor Regression without Loss of Target Antigens or IFN gamma Signaling
- 2017
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Ingår i: Cancer Research. - : American Association for Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 77:17, s. 4562-4566
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Tidskriftsartikel (refereegranskat)abstract
- Cancer immunotherapy can result in durable tumor regressions in some patients. However, patients who initially respond often experience tumor progression. Here, we report mechanistic evidence of tumoral immune escape in an exemplary clinical case: a patient with metastatic melanoma who developed disease recurrence following an initial, unequivocal radiologic complete regression after T-cell-based immunotherapy. Functional cytotoxic T-cell responses, including responses to one mutant neoantigen, were amplified effectively with therapy and generated durable immunologic memory. However, these immune responses, including apparently effective surveillance of the tumor mutanome, did not prevent recurrence. Alterations of the MHC class I antigen-processing and presentation machinery (APM) in resistant cancer cells, but not antigen loss or impaired IFN gamma signaling, led to impaired recognition by tumor-specific CD8(+) T cells. Our results suggest that future immunotherapy combinations should take into account targeting cancer cells with intact and impaired MHC class I-related APM. Loss of target antigens or impaired IFN gamma signaling does not appear to be mandatory for tumor relapse after a complete radiologic regression. Personalized studies to uncover mechanisms leading to disease recurrence within each individual patient are warranted.
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| 6. |
- Fortner, Renée T, et al.
(författare)
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Human Chorionic Gonadotropin Does Not Correlate with Risk for Maternal Breast Cancer : Results from the Finnish Maternity Cohort
- 2017
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 77:1, s. 134-141
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Tidskriftsartikel (refereegranskat)abstract
- Human chorionic gonadotropin (hCG) is necessary for the maintenance of early pregnancy and promotes normal breast cell differentiation. Administered hCG reduces risk of carcinogen-induced breast cancer in animal models, and higher circulating hCG concentrations were associated with significantly lower long-term risk of breast cancer in a prior nested case-control study. In this study, we investigated early-pregnancy hCG concentrations and subsequent breast cancer risk. We conducted a nested case-control study with 1,191 cases and 2,257 controls (matched on age and date at blood collection) in the Finnish Maternity Cohort, a cohort with serum samples from 98% of pregnancies registered in Finland since 1983. This study included women with a serum sample collected early (<140 days gestation) in their first pregnancy resulting in a live, term birth. Breast cancer cases were identified via the Finnish Cancer Registry. Age at breast cancer diagnosis ranged from 22 to 58 years (mean: 41 years). hCG was measured using a solid-phase competitive chemiluminescence assay. Odds ratios (OR) were calculated using conditional logistic regression. We observed no association between hCG and breast cancer risk, overall [Quartile 4 vs. 1, OR, 1.14; 95% confidence interval (CI), 0.94-1.39], by estrogen and progesterone receptor status, or by ages at first-term birth or diagnosis. Associations did not differ by time between pregnancy and diagnosis (e.g., <5 years, ORQ4 vs. Q1, 1.10; 95% CI, 0.64-1.89; ≥15 years, ORQ4 vs. Q1, 1.36; 95% CI, 0.86-2.13; pheterogeneity = 0.62). This large prospective study does not support an inverse relationship between early pregnancy serum hCG concentrations and breast cancer risk.
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| 7. |
- Gustafsson, Robert, et al.
(författare)
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Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor
- 2017
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Ingår i: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 77:4, s. 937-948
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Tidskriftsartikel (refereegranskat)abstract
- To sustain their proliferation, cancer cells become dependent on one-carbon metabolism to support purine and thymidylate synthesis. Indeed, one of the most highly upregulated enzymes during neoplastic transformation is MTHFD2, a mitochondrial methylenetetrahydrofolate dehydrogenase and cyclohydrolase involved in one-carbon metabolism. Because MTHFD2 is expressed normally only during embryonic development, it offers a disease-selective therapeutic target for eradicating cancer cells while sparing healthy cells. Here we report the synthesis and preclinical characterization of the first inhibitor of human MTHFD2. We also disclose the first crystal structure of MTHFD2 in complex with a substrate-based inhibitor and the enzyme cofactors NAD(+) and inorganic phosphate. Our work provides a rationale for continued development of a structural framework for the generation of potent and selective MTHFD2 inhibitors for cancer treatment.
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| 8. |
- Mathot, Lucy, et al.
(författare)
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Somatic Ephrin Receptor Mutations Are Associated with Metastasis in Primary Colorectal Cancer
- 2017
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 77:7, s. 1730-1740
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Tidskriftsartikel (refereegranskat)abstract
- The contribution of somatic mutations to metastasis of colorectal cancers is currently unknown. To find mutations involved in the colorectal cancer metastatic process, we performed deep mutational analysis of 676 genes in 107 stages II to IV primary colorectal cancer, of which half had metastasized. The mutation prevalence in the ephrin (EPH) family of tyrosine kinase receptors was 10-fold higher in primary tumors of metastatic colorectal than in nonmetastatic cases and preferentially occurred in stage III and IV tumors. Mutational analyses in situ confirmed expression of mutant EPH receptors. To enable functional studies of EPHB1 mutations, we demonstrated that DLD-1 colorectal cancer cells expressing EPHB1 form aggregates upon coculture with ephrin B1 expressing cells. When mutations in the fibronectin type III and kinase domains of EPHB1 were compared with wild-type EPHB1 in DLD-1 colorectal cancer cells, they decreased ephrin B1-induced compartmentalization. These observations provide a mechanistic link between EPHB receptor mutations and metastasis in colorectal cancer.
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| 9. |
- Niklasson, Mia, et al.
(författare)
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Membrane-Depolarizing Channel Blockers Induce Selective Glioma Cell Death by Impairing Nutrient Transport and Unfolded Protein/Amino Acid Responses
- 2017
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Ingår i: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 77:7, s. 1741-1752
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Tidskriftsartikel (refereegranskat)abstract
- Glioma-initiating cells (GIC) are considered the underlying cause of recurrences of aggressive glioblastomas, replenishing the tumor population and undermining the efficacy of conventional chemotherapy. Here we report the discovery that inhibiting T-type voltage-gated Ca2+ and KCa channels can effectively induce selective cell death of GIC and increase host survival in an orthotopic mouse model of human glioma. At present, the precise cellular pathways affected by the drugs affecting these channels are unknown. However, using cell-based assays and integrated proteomics, phosphoproteomics, and transcriptomics analyses, we identified the downstreamsignaling events these drugs affect. Changes in plasma membrane depolarization and elevated intracellular Na+, which compromised Na+-dependent nutrient transport, were documented. Deficits in nutrient deficit acted in turn to trigger the unfolded protein response and the amino acid response, leading ultimately to nutrient starvation and GIC cell death. Our results suggest new therapeutic targets to attack aggressive gliomas.
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| 10. |
- Ose, Jennifer, et al.
(författare)
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Androgens Are Differentially Associated with Ovarian Cancer Subtypes in the Ovarian Cancer Cohort Consortium
- 2017
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 77:14, s. 3951-3960
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Tidskriftsartikel (refereegranskat)abstract
- Invasive epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The etiology of EOC remains elusive; however, experimental and epidemiologic data suggest a role for hormone-related exposures in ovarian carcinogenesis and risk factor differences by histologic phenotypes and developmental pathways. Research on prediagnosis androgen concentrations and EOC risk has yielded inconclusive results, and analyses incorporating EOC subtypes are sparse. We conducted a pooled analysis of 7 nested case–control studies in the Ovarian Cancer Cohort Consortium to investigate the association between pre-diagnosis circulating androgens [testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS)], sex hormone binding globulin (SHBG), and EOC risk by tumor characteristics (i.e., histology, grade, and stage). The final study population included 1,331 EOC cases and 3,017 matched controls. Multivariable conditional logistic regression was used to assess risk associations in pooled individual data. Testosterone was positively associated with EOC risk (all subtypes combined, ORlog2 = 1.12; 95% confidence interval 1.02–1.24); other endogenous androgens and SHBG were not associated with overall risk. Higher concentrations of testosterone and androstenedione associated with an increased risk in endometrioid and mucinous tumors [e.g., testosterone, endometrioid tumors, ORlog2 = 1.40 (1.03–1.91)], but not serous or clear cell. An inverse association was observed between androstenedione and high grade serous tumors [ORlog2 = 0.76 (0.60–0.96)]. Our analyses provide further evidence for a role of hormone-related pathways in EOC risk, with differences in associations between androgens and histologic subtypes of EOC.
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