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Endometrial luminal epithelium transcriptome during early diestrus defines pregnancy outcome in cattle

ABSTRACT: Endometrial luminal epithelium transcriptome during early diestrus defines pregnancy outcome in cattle

PROVIDER: PRJNA720121 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14154300_1.fastq.gz	Fastqsanger.gz
	SRR14154300_2.fastq.gz	Fastqsanger.gz
	SRR14154301_1.fastq.gz	Fastqsanger.gz
	SRR14154301_2.fastq.gz	Fastqsanger.gz
	SRR14154302_1.fastq.gz	Fastqsanger.gz

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Project description:Background: Breast cancer is a heterogeneous disease at the clinical and molecular level. In this study we integrate classifications extracted from five different molecular levels in order to identify integrated subtypes. Methods: Tumor tissue from 425 primary breast cancer patients of the Oslo2 study was cut and blended before being divided into fractions for DNA-, RNA- and protein isolation, and metabolomics, allowing for representative and comparable molecular data. Patients were stratified into groups based on their tumor characteristics from five different molecular levels, using various clustering methods. Finally, all previously identified and newly determined subgroups were combined in a multilevel classification using a “cluster-of-clusters” approach with consensus clustering. Results: Based on DNA copy number data, tumors were scored into three groups according to the complex arm aberration index. mRNA expression profiles divided tumors into five molecular subgroups according to PAM50 subtyping, and clustering based on microRNA expression revealed four subgroups. Reverse-phase protein array data divided tumors into five subgroups. Hierarchical clustering of tumor metabolic profiles revealed three clusters. Combining DNA copy number and mRNA expression classified tumors into seven clusters based on pathway activity levels, and using integrative clustering, tumors were classified into ten subtypes. The final consensus clustering incorporating all the aforementioned subtypes revealed six major groups. Five corresponded well with the mRNA subtypes, while a sixth group resulted from a split of the luminal A subtype where these tumors belonged to distinct microRNA clusters. Gain-of-function studies using MCF-7 cells showed that microRNAs differentially expressed between the luminal A clusters were important for cancer cell survival. These microRNAs were used to validate the split in luminal A tumors in four independent breast cancer cohorts. In two cohorts the microRNAs divided tumors into subgroups with significant different outcome, and in another a trend was observed. Conclusions: The herein identified six integrated subtypes confirm the heterogeneity of breast cancer and show that finer subdivisions of subtypes are evident. Increasing the knowledge of the luminal A subtype heterogeneity may add pivotal information guiding therapeutic choices, evidently bringing us closer to more personalized treatment for this largest subgroup of breast cancer.

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Endometrial luminal epithelium transcriptome during early diestrus defines pregnancy outcome in cattle

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