Loss of function of BRCA1 promotes EMT in mammary tumors through activation of TGF\u03b2R2 signaling pathway

Feng Bai,Xin-Hai Pei,Chuying Wang,Shiqin Liu,Daniel Hollern,Jason I Herschkowitz,Sijia Ren,Chang Liu,Wei-Guo Zhu,Xiong Liu,Cheng Fan

doi:10.1038/s41419-022-04646-7

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.

Highlights

Breast cancer comprises three main subtypes: human epidermal growth factor receptor 2 (HER2) positive breast cancer, hormone receptor [estrogen receptor (ER) and/or progesterone receptor (PgR)]-positive breast cancer, and triple-negative breast cancer (TNBC), the latter of which lacks expression of ER, PgR, and HER2 [1, 2]
Germline deletion of Brca1 activates Tgfβ signaling and epithelial to mesenchymal transition (EMT) with enhanced expression of Tgfβr2 in mammary tumor cells phenotype with EMT features
We previously demonstrated that heterozygous germline deletion of Brca1 in p18 null mice activated EMT and led to Basal-like breast cancer (BLBC) with protein levels, as well as the level of phosphorylated-Smad2, were significantly increased in p18−/−; Brca1MGKO tumors enhanced cancer stem cell (CSC) populations along with the increased potential for metastasis {Figs. 1A, S1A–C, and details in [18, 19, 22]}

Summary

Introduction

Breast cancer comprises three main subtypes: human epidermal growth factor receptor 2 (HER2) positive breast cancer, hormone receptor [estrogen receptor (ER) and/or progesterone receptor (PgR)]-positive breast cancer, and triple-negative breast cancer (TNBC), the latter of which lacks expression of ER, PgR, and HER2 [1, 2]. Gene-expression analyses have categorized human breast tumor into six intrinsic subtypes: basal-like (BL), claudin-low (CL), Her2-enriched, luminal A, luminal B, and normal breast-like, each of which has unique biological and prognostic features [3]. Of these subtypes of breast cancer, the CL subtype is a TNBC characterized by the high enrichment for epithelial to mesenchymal transition (EMT) markers and cancer stem cell (CSC)-like features [3, 4]. The high mortality rate of BLBCs can be attributed to the aggressive and metastatic capacity of these tumors and the limited number of effective therapeutic options. While some molecular regulators of EMT have been identified [10], therapeutically targetable mechanisms controlling EMT in BLBCs remain elusive

Methods

Results

Conclusion