TGF\u03b2/cyclin D1/Smad-mediated inhibition of BMP4 promotes breast cancer stem cell self-renewal activity

Gang Yan,Meiou Dai,Chenjing Zhang,Sophie Poulet,Jean-Jacques Lebrun,Julien Boudreault,Suhad Ali,Alaa Moamer,Ni Wang

doi:10.1038/s41389-021-00310-5

Abstract

Basal-like triple-negative breast cancers (TNBCs) display poor prognosis, have a high risk of tumor recurrence, and exhibit high resistance to drug treatments. The TNBC aggressive features are largely due to the high proportion of cancer stem cells present within these tumors. In this study, we investigated the interplay and networking pathways occurring between TGFβ family ligands in regulating stemness in TNBCs. We found that TGFβ stimulation of TNBCs resulted in enhanced tumorsphere formation efficiency and an increased proportion of the highly tumorigenic CD44high/CD24low cancer stem cell population. Analysis of the TGFβ transcriptome in TNBC cells revealed bone morphogenetic protein4 (BMP4) as a main TGFβ-repressed target in these tumor cells. We further found that BMP4 opposed TGFβ effects on stemness and potently decreased cancer stem cell numbers, thereby acting as a differentiation factor in TNBC. At the molecular level, we found that TGFβ inhibition of BMP4 gene expression is mediated through the Smad pathway and cyclin D1. In addition, we also found BMP4 to act as a pro-differentiation factor in normal mammary epithelial cells and promote mammary acinar formation in 3D cell culture assays. Finally, and consistent with our in vitro results, in silico patient data analysis defined BMP4 as a potential valuable prognosis marker for TNBC patients.

Highlights

Triple-negative breast cancers (TNBCs) represent10–20% of all breast cancers and are characterized by negative or low estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression[1]
Many reports have indicated that Breast cancer stem cells (BCSCs) are associated with resistance to conventional therapies such as chemotherapy or radiotherapy, and have the ability to regrow tumors resulting in later relapse of breast cancer patients[55,56]
A better understanding of the molecular mechanisms underlying the regulation of stem-like properties of BCSCs and identification of the upstream growth factor signaling pathways that control these events will be instrumental for the development of novel clinical therapeutic strategies against TNBC

Summary

Introduction

10–20% of all breast cancers and are characterized by negative or low estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression[1]. Based on their gene expression profiles, the majority of TNBCs are classified as basal-like breast cancers. This molecular subtype is often associated with larger tumor size, higher tumor grade, greater lymph node spread, and a higher rate of distant metastasis[2,3]. Cancer stem cells (CSCs) or tumor-initiating cells represent a distinct subpopulation of cancer cells within the tumor, that possess stem cell-like properties[9]

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