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Prognostic Value of Stromal Type IV Collagen Expression in Small Invasive Breast Cancers
Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.ORCID-id: 0000-0003-2624-4671
Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet, Statistik. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.ORCID-id: 0000-0002-8601-0159
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2022 (Engelska)Ingår i: Frontiers in Molecular Biosciences, E-ISSN 2296-889X, Vol. 9, artikel-id 904526Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Breast cancer is the most common cause of cancer death among women worldwide. Localized breast cancer can be cured by surgery and adjuvant therapy, but mortality remains high for tumors that metastasize early. Type IV collagen is a basement membrane protein, and breach of this extracellular matrix structure is the first step of cancer invasion. Type IV collagen is found in the stroma of many cancers, but its role in tumor biology is unclear. Here, expression of type IV collagen in the stroma of small breast cancers was analyzed, correlated to clinically used prognostic biomarkers and patient survival. The findings were further validated in an independent gene expression data cohort. Tissue samples from 1,379 women with in situ and small invasive breast cancers (≤15 mm) diagnosed in 1986-2004 were included. Primary tumor tissue was collected into tissue microarrays. Type IV collagen expression in tissues was visualized using immunohistochemistry. Gene expression data was extracted from the Cancer Genome Atlas database. Out of 1,379 women, 856 had an invasive breast cancer and type IV collagen staining was available for 714 patients. In Kaplan-Meier analysis high type IV collagen expression was significantly associated (p = 0.026) with poorer breast cancer specific survival. There was no correlation of type IV collagen expression to clinically used prognostic biomarkers. High type IV collagen expression was clearly associated to distant metastasis (p = 0.002). In an external validation cohort (n = 1,104), high type IV collagen mRNA expression was significantly (p = 0.041) associated with poorer overall survival, with overexpression of type IV collagen mRNA in metastatic tissue. Stromal type IV collagen expression in the primary tumor correlates to poor breast cancer specific survival most likely due to a higher risk of developing distant metastasis. This ECM protein may function as biomarker to predict the risk of future metastatic disease in patients with breast cancers.

Ort, förlag, år, upplaga, sidor
Frontiers Media S.A., 2022. Vol. 9, artikel-id 904526
Nyckelord [en]
breast cancer, extracellular matrix, tumor microenvironment, tumor progression, type IV collagen
Nationell ämneskategori
Kirurgi
Identifikatorer
URN: urn:nbn:se:umu:diva-200221DOI: 10.3389/fmolb.2022.904526ISI: 000807868300001PubMedID: 35693557Scopus ID: 2-s2.0-85131874326OAI: oai:DiVA.org:umu-200221DiVA, id: diva2:1703116
Forskningsfinansiär
Region Västerbotten, 93242Region Västerbotten, 866131Region Västerbotten, 764621Visare Norr, 931408Visare Norr, 750491BröstcancerfondenTillgänglig från: 2022-10-12 Skapad: 2022-10-12 Senast uppdaterad: 2023-09-26Bibliografiskt granskad
Ingår i avhandling
1. The role of stroma-derived substances in breast cancer progression and their function as tumour markers
Öppna denna publikation i ny flik eller fönster >>The role of stroma-derived substances in breast cancer progression and their function as tumour markers
2022 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Alternativ titel[sv]
Kartläggning av tumör-stroma associerade substanser och deras roll vid bröstcancerprogression och som tumörmarkörer
Abstract [en]

Background: In 2020, more than 2,260,000 women were diagnosed with breast cancer. Most patients are cured with surgery and adjuvant treatment, but despite that, approximately 700,000 women die of the disease every year. The historical focus on breast cancer progression has been on the malignant epithelial cell. However, cancer cells do not grow in isolation. In recent years, the importance of the tumour microenvironment in cancer progression has been highlighted. Perlecan and type IV collagen are basement membrane (BM) proteins in the normal mammary gland, and type I collagen is the main fibrillar collagen in the interstitial extracellular matrix (ECM). In cancer development, perlecan and type IV collagen have multifunctional roles and when degraded from the BM, bioactive substances and other fragments are released in the circulation. Significant ECM changes also occur that lead to an accumulation of fibrillar collagens. Given their abundance in the ECM; perlecan, type IV and type I collagen are of interest for breast cancer progression and may be of importance as new biomarkers to monitor disease, predict patient outcome and the treatment effect.

Aim: In this thesis, the protein and mRNA expression of perlecan, type IV and I collagen in breast cancer tissue is studied. The aim is to characterize the expression pattern of these proteins in breast cancer tissue and to see whether there is a correlation to known prognostic biomarkers and to the patient prognosis. Moreover, to evaluate circulating perlecan and type IV collagen as diagnostic and prognostic biomarkers in breast cancer patients.

Methods: In this thesis project, eight different patient cohorts were used. In freshly frozen normal breast and breast cancer tissue, perlecan protein expression was visualized using immunofluorescence. Type IV and I collagen protein expression were studied with immunohistochemistry in formalin-fixed, paraffin embedded primary breast cancer tissue, and type IV collagen in metastatic breast cancer tissue. For gene expression analysis, mRNA and clinicopathological data were extracted from the Cancer Genome Atlas and cBioportal database. Circulating plasma levels of perlecan were analysed in breast cancer patients and controls, circulating levels of CA15-3 and type IV collagen in patients with primary and metastatic breast cancer as well as controls. Perlecan and type IV collagen were measured with ELISA assays, and CA15-3 were using an electrochemiluminescence immunoassay.

Results: In breast cancer tissue, perlecan and type IV collagen protein expression in the epithelial BM was fragmented or completely lost, and perlecan and type IV collagen was expressed to varying extent in the tumour stroma. The mRNA analysis confirmed that type IV collagen mRNA was expressed in primary breast cancer tissue and highly expressed in metastatic tissue. Type I collagen was mostly highly expressed in the tumour stroma. Low type I collagen protein and mRNA expression correlated with biomarkers for aggressive breast cancer, but no effect on survival could be seen. Among patients receiving chemotherapy, low stromal type I collagen protein expression was associated with better survival compared to high expression, even after adjusting for other relevant factors. There was no correlation of perlecan or type IV collagen protein expression to clinically used prognostic biomarkers, but an oestrogen receptor dependent correlation between mRNA expression of perlecan and several matrix-degrading enzymes were found. Survival analysis showed that high stromal type IV collagen protein and mRNA expression in the primary tumour was significantly associated with a poorer survival, and high protein expression with a risk of developing distant metastasis. Metastatic breast cancer patients had higher levels of circulating type IV collagen compared to healthy controls and patients with primary breast cancer. High circulating type IV collagen levels correlated with poorer survival in metastatic breast cancer patients, and was superior to CA15-3 at detecting metastatic breast cancer.

Conclusions: The protein expression pattern of perlecan, type IV collagen and type I collagen become abnormal during breast cancer development. Stromal type IV collagen protein and mRNA in the primary tumour correlates to poorer prognosis, most likely due to a higher risk of developing metastatic disease. Circulating type IV collagen can function as a biomarker for detecting metastatic disease in patients with primary breast cancer and is prognostic in patients with metastatic breast cancer. Low stromal type I collagen is a marker for an aggressive breast cancer disease and can predict chemotherapy response.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå universitet, 2022. s. 63
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 2197
Nyckelord
Breast cancer, perlecan, type IV collagen, type I collagen, extracellular matrix, tumour biomarkers
Nationell ämneskategori
Cancer och onkologi Kirurgi
Forskningsämne
kirurgi
Identifikatorer
urn:nbn:se:umu:diva-200224 (URN)978-91-7855-861-2 (ISBN)978-91-7855-862-9 (ISBN)
Disputation
2022-11-18, Lionsalen, Byggnad 7, Norrlands Universitetssjukhus, Umeå, 13:00 (Svenska)
Opponent
Handledare
Tillgänglig från: 2022-10-28 Skapad: 2022-10-12 Senast uppdaterad: 2022-10-18Bibliografiskt granskad

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Jansson, MalinRask, GunillaSvensson, JohanBilling, OlaNazemroaya, AnooshehBerglund, AnetteSund, Malin

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