A shared transcriptional landscape between human breast cancers and breast cancers induced by genetic modeling of viral infection in mice.

Mapping Intimacies ◽

10.31219/osf.io/8uzcq ◽

2020 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Breast Cancer ◽

Viral Infection ◽

Differentially Expressed Genes ◽

Mammary Tumor ◽

Human Breast Cancer ◽

Differentially Expressed ◽

Breast Cancers ◽

Human Breast ◽

Transgenic Expression ◽

Genetic Modeling

We recently demonstrated, through analysis of published transcriptome data from human and murine breast cancer that eight genes whose expression was most different in tumors that arise in the mouse breast following transgenic expression of the SV40 large T-antigen or modeling of integration following infection with multiple mammary tumor viruses, including CD36, ASPM, PDGFD and CEP55 were also among the genes most differentially expressed in the primary tumors of humans with breast cancer (1). We report here that these transcriptional similarities are a much larger phenomena, with 45-54% of the top one hundred most differentially expressed genes in murine breast cancer resulting from genetic modeling of viral infection with the murine mammary tumor virus MMTV or transgenic expression of SV40 large T also among the most differentially expressed genes in human breast cancer. Despite inherent differences in transcription due to species divergence, blind whole transcriptome (2-4) analyses reveals striking transcriptional similarity in the landscape of human breast cancer and murine breast cancers resulting from genetic modeling of viral infection, providing further evidence to support the hypothesis that one or more viral agents with transformation capacity may contribute to the development of human breast cancer.

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A DREAM complex gene expression program involving E2F4, E2F6, SIN3A and NFYB in human breast cancer and in murine breast cancers arising from genetic modeling of transformation induced by viral infection.

10.31219/osf.io/emywp ◽

2020 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Viral Infection ◽

Human Breast Cancer ◽

Gene Expression Program ◽

Differentially Expressed ◽

Breast Cancers ◽

Human Breast ◽

Genetic Modeling ◽

Expression Program

We recently reported that nearly half of the most differentially expressed genes in the the breast tumors of mice resulting from genetic modeling of integration events or oncogene expression occurring during viral infection by viruses including the murine mammary tumor virus, SV40 and polyomavirus are also significantly differentially expressed in human breast cancer, the majority of which are of unknown etiology (1, 2). Here we present evidence of the existence of a gene expression program operating through the DREAM complex, E2F transcription factors E2F4 and E2F6, as well as NFYB and SIN3A, both in the tumors of mice resulting from genetic modeling of viral infection and in the primary tumors of human patients with breast cancer through blind analysis of published whole transcriptome data (3-5). The similarity between human breast cancer and cancers induced by genetic engineering of integration events and oncogene expression in mice is not limited to differential expression of single genes in isolation, nor multiple numbers of single genes; a centrally regulated, major transcriptional network is perturbed in a mirrored fashion in human breast cancer and virally-induced breast cancers in mice.

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Infection of the kidneys with the BK polyomavirus is associated with transcriptional induction of PSMB9 and IGFLR1, genes differentially expressed in human breast cancer.

10.31219/osf.io/7gurv ◽

2020 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Breast Cancer ◽

Differentially Expressed Genes ◽

Human Breast Cancer ◽

T Antigen ◽

Bk Virus ◽

Differentially Expressed ◽

Breast Cancers ◽

Human Breast ◽

Bk Polyomavirus ◽

Transcriptional Modulation

The BK polyomavirus is both the cause of nephropathy in kidney transplant patients (1-3) and one of many viruses whose presence has previously been investigated in the tumors of patients with breast cancer (4, 5). We mined published microarray data (6, 7) to identify differentially expressed genes associated with BK polyomavirus infection of the kidneys in patients with transplant-associated nephropathy, integrating these findings with whole transcriptome analysis of human breast cancers to determine the presence of differentially expressed genes in breast cancers whose expression was significantly modulated by BK virus infection. We identified conserved transcriptional modulation of the IGF-like family receptor 1 (IGFLR1) and the proteasome subunit 9 (PSMB9) in the kidneys of patients with transplant-associated nephropathy and in the primary tumors of patients with breast cancer. These data demonstrate the existence of common transcriptional modulation in human breast cancer and in the kidneys associated with BK virus, and provide rationale for evaluation of BK virus large T-antigen expression in the human breast during breast cancer.

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Transcriptional similarities between human breast cancers and breast cancers resulting from genetic modeling of viral infection in mice.

10.31219/osf.io/eqdaj ◽

2020 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Breast Cancer ◽

Viral Infection ◽

Experimental Evidence ◽

Human Breast Cancer ◽

Breast Tissue ◽

Genetically Engineered ◽

Breast Cancers ◽

Human Breast ◽

Primary Tumors ◽

Genetic Modeling

Breast cancer affects women in the United States and worldwide at relatively high frequency (1). Mutations in BRCA1 have been identified as a cause of breast cancer in a minority of patients with the familiar or inherited form of breast cancer (2, 3), but it remains unknown what factor or factors trigger development of breast cancer in the vast majority of women. It has been suggested that infection with a spectrum of viruses, including DNA tumor viruses like human papillomavirus and SV40, and retroviruses like the mouse mammary tumor virus (MMTV) can be associated with human breast cancer (4-6) but experimental evidence to support the claim that viral infections cause human breast cancer is lacking. We evaluated the hypothesis that primary tumors from humans with breast cancers will share transcriptional similarity at the systems level with experimental breast cancers induced by genetic modeling of viral infection or transgenic expression of a viral oncoprotein by mining published microarray data (7-9). We identified, in a blind fashion, eight independent genes with crucial functions in cancer cell survival among the most differentially expressed genes transcriptome-wide, including genes not previously implicated in human breast cancer, both when comparing normal breast tissue and primary tumors from women with breast cancer, and when comparing breast tissue to breast tumors from 5 independent strains of mice genetically engineered to model viral induction of transformation in the mammalian breast, including MMTV-PyMT, MMTV-Wnt11 and the large T-antigen of SV40. These marked transcriptional changes between breast and tumor were not only shared by humans with breast cancer and breast cancer resulting from genetic modeling of viral integration or oncogene expression events in mice, but also by mice genetically engineered to model familial breast cancer, lacking BRCA1 and one copy of the tumor suppressor p53. These data demonstrate that key changes in the human breast cancer tumor transcriptome are also found in mice that develop breast cancer as a direct result of viral infection, and are one piece of experimental evidence, obtained through unbiased methods, to support the assertion that viral infection can contribute to breast cancer in humans.

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