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Mouse Mammary Tumor Virus (MMTV)-Like env Sequence in Brazilian Breast Cancer Samples: Implications in Clinicopathological Parameters in Molecular Subtypes.

ABSTRACT: Background: Breast cancer (BC) is a complex disease in which susceptibility and clinical course depend on multiple factors. Evidence suggests that a mouse mammary tumor virus (MMTV)-homolog may be present in human BCs; however, little is known about its clinical implications. Methods: MMTV-like env nucleotide-sequence was searched in tumor and tumor-adjacent tissues from 217 Brazilian BC patients through nested-PCR and confirmed through PCR-sequencing. Blood samples were also tested for patients with MMTV-like env gene-positive tumors. Correlations with clinicopathological parameters were evaluated. Results: MMTV-like env sequence was detected in tumor and tumor-adjacent tissue samples from 41/217 and 30/196 patients, respectively. In blood, MMTV-like was detected in 17/32 patients. In Luminal-B tumors, MMTV-like in tumor tissue was negatively correlated with tumor size and disease stage, whereas in HER2 tumors it anti-correlated with lymph node metastasis (LNM) and disease stage. Considering blood, MMTV-like env gene positivity negatively correlated with age in general BC, while in Luminal-A tumors it positively correlated with Ki67 but negatively correlated with age and LNM. The associations with decreased LNM frequency were independent of other prognostic factors. Conclusion: MMTV-like env positivity is associated with better prognostic parameters in BC subtypes, which might be explainable by its anti-metastatic potential and by putative activation of immune milieu.

SUBMITTER: de Sousa Pereira N

PROVIDER: S-EPMC7766913 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Mouse Mammary Tumor Virus (MMTV)-Like env Sequence in Brazilian Breast Cancer Samples: Implications in Clinicopathological Parameters in Molecular Subtypes.

de Sousa Pereira Nathália N Akelinghton Freire Vitiello Glauco G Karina Banin-Hirata Bruna B Scantamburlo Alves Fernandes Glaura G José Sparça Salles Maria M Karine Amarante Marla M Angelica Ehara Watanabe Maria M

International journal of environmental research and public health 20201218 24

Background: Breast cancer (BC) is a complex disease in which susceptibility and clinical course depend on multiple factors. Evidence suggests that a mouse mammary tumor virus (MMTV)-homolog may be present in human BCs; however, little is known about its clinical implications. Methods: MMTV-like env nucleotide-sequence was searched in tumor and tumor-adjacent tissues from 217 Brazilian BC patients through nested-PCR and confirmed through PCR-sequencing. Blood samples were als ...[more]

PMID: 33352945

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Project description:BACKGROUND:PIK3CA mutations are frequent in human breast cancer. Pik3caH1047R mutant expression in mouse mammary gland promotes tumorigenesis. TP53 mutations co-occur with PIK3CA mutations in human breast cancers. We previously generated a conditionally activatable Pik3caH1047R;MMTV-Cre mouse model and found a few malignant sarcomatoid (spindle cell) carcinomas that had acquired spontaneous dominant-negative Trp53 mutations. METHODS:A Pik3caH1047R;Trp53R270H;MMTV-Cre double mutant mouse breast cancer model was generated. Tumors were characterized by histology, marker analysis, transcriptional profiling, single-cell RNA-seq, and bioinformatics. Cell lines were developed from mutant tumors and used to identify and confirm genes involved in metastasis. RESULTS:We found Pik3caH1047R and Trp53R270H cooperate in driving oncogenesis in mammary glands leading to a shorter latency than either alone. Double mutant mice develop multiple histologically distinct mammary tumors, including adenocarcinoma and sarcomatoid (spindle cell) carcinoma. We found some tumors to be invasive and a few metastasized to the lung and/or the lymph node. Single-cell RNA-seq analysis of the tumors identified epithelial, stromal, myeloid, and T cell groups. Expression analysis of the metastatic tumors identified S100a4 as a top candidate gene associated with metastasis. Metastatic tumors contained a much higher percentage of epithelial-mesenchymal transition (EMT)-signature positive and S100a4-expressing cells. CRISPR/CAS9-mediated knockout of S100a4 in a metastatic tumor-derived cell line disrupted its metastatic potential indicating a role for S100a4 in metastasis. CONCLUSIONS:Pik3caH1047R;Trp53R270H;MMTV-Cre mouse provides a preclinical model to mimic a subtype of human breast cancers that carry both PIK3CA and TP53 mutations. It also allows for understanding the cooperation between the two mutant genes in tumorigenesis. Our model also provides a system to study metastasis and develop therapeutic strategies for PIK3CA/TP53 double-positive cancers. S100a4 found involved in metastasis in this model can be a potential diagnostic and therapeutic target.

Dataset Information

Mouse Mammary Tumor Virus (MMTV)-Like env Sequence in Brazilian Breast Cancer Samples: Implications in Clinicopathological Parameters in Molecular Subtypes.

Publications

Mouse Mammary Tumor Virus (MMTV)-Like <i>env</i> Sequence in Brazilian Breast Cancer Samples: Implications in Clinicopathological Parameters in Molecular Subtypes.

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