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Loss of function of BRCA1 promotes EMT in mammary tumors through activation of TGFβR2 signaling pathway.

ABSTRACT: BRCA1 deficient breast cancers are aggressive and chemoresistant due, in part, to their enrichment of cancer stem cells that can be generated from carcinoma cells by an epithelial-mesenchymal transition (EMT). We previously discovered that BRCA1 deficiency activates EMT in mammary tumorigenesis. How BRCA1 controls EMT and how to effectively target BRCA1-deficient cancers remain elusive. We analyzed murine and human tumors and identified a role for Tgfβr2 in governing the molecular aspects of EMT that occur with Brca1 loss. We utilized CRISPR to delete Tgfβr2 and specific inhibitors to block Tgfβr2 activity and followed up with the molecular analysis of assays for tumor growth and metastasis. We discovered that heterozygous germline deletion, or epithelia-specific deletion of Brca1 in mice, activates Tgfβr2 signaling pathways in mammary tumors. BRCA1 depletion promotes TGFβ-mediated EMT activation in cancer cells. BRCA1 binds to the TGFβR2 locus to repress its transcription. Targeted deletion or pharmaceutical inhibition of Tgfβr2 in Brca1-deficient tumor cells reduces EMT and suppresses tumorigenesis and metastasis. BRCA1 and TGFβR2 expression levels are inversely related in human breast cancers. This study reveals for the first time that a targetable TGFβR signaling pathway is directly activated by BRCA1-deficiency in the induction of EMT in breast cancer progression.

SUBMITTER: Bai F

PROVIDER: S-EPMC8891277 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Loss of function of BRCA1 promotes EMT in mammary tumors through activation of TGFβR2 signaling pathway.

Bai Feng F Wang Chuying C Liu Xiong X Hollern Daniel D Liu Shiqin S Fan Cheng C Liu Chang C Ren Sijia S Herschkowitz Jason I JI Zhu Wei-Guo WG Pei Xin-Hai XH

Cell death & disease 20220302 3

BRCA1 deficient breast cancers are aggressive and chemoresistant due, in part, to their enrichment of cancer stem cells that can be generated from carcinoma cells by an epithelial-mesenchymal transition (EMT). We previously discovered that BRCA1 deficiency activates EMT in mammary tumorigenesis. How BRCA1 controls EMT and how to effectively target BRCA1-deficient cancers remain elusive. We analyzed murine and human tumors and identified a role for Tgfβr2 in governing the molecular aspects of EMT ...[more]

PMID: 35236825

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Project description:Purpose: GATA3 is a transcription factor essential for mammary luminal epithelial cell differentiation. Expression of GATA3 is absent or significantly reduced in basal-like breast cancers. Gata3 loss-of-function impairs cell proliferation, making it difficult to investigate the role of GATA3 deficiency in vivo. We previously demonstrated that CDK inhibitor p18INK4c (p18) is a downstream target of GATA3 and restrains mammary epithelial cell proliferation and tumorigenesis. Whether and how loss-of-function of GATA3 results in basal-like breast cancers remains elusive. Methods: We generated mutant mouse strains with heterozygous germline deletion of Gata3 in p18 deficient backgrounds and developed a Gata3 depleted mammary tumor model system to determine the role of Gata3 loss in controlling cell proliferation and aberrant differentiation in mammary tumor development and progression. Results: Haploid loss of Gata3 reduced mammary epithelial cell proliferation with induction of p18, impaired luminal differentiation, and promoted basal differentiation in mammary glands. p18 deficiency induced luminal type mammary tumors and rescued the proliferative defect caused by haploid loss of Gata3. Haploid loss of Gata3 accelerated p18 deficient mammary tumor development and changed the properties of these tumors, resulting in their malignant and luminal-to-basal transformation. Expression of Gata3 negatively correlated with basal differentiation markers in MMTV-PyMT mammary tumor cells. Depletion of Gata3 in luminal tumor cells also reduced cell proliferation with induction of p18 and promoted basal differentiation. We confirmed that expression of GATA3 and basal markers are inversely correlated in human basal-like breast cancers. Conclusions: This study provides the first genetic evidence demonstrating that loss-of-function of GATA3 directly induces basal-like breast cancer. Our finding suggests that basal-like breast cancer may also originate from luminal type cancer.

Dataset Information

Loss of function of BRCA1 promotes EMT in mammary tumors through activation of TGFβR2 signaling pathway.

Publications

Loss of function of BRCA1 promotes EMT in mammary tumors through activation of TGFβR2 signaling pathway.

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