ID2 and GJB2 promote early-stage breast cancer progression by regulating cancer stemness
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Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer which could progress to or recur as invasive breast cancer. The underlying molecular mechanism of DCIS progression is yet poorly understood, and appropriate biomarkers to distinguish benign form of DCIS from potentially invasive tumor are urgently needed.
To identify the key regulators of DCIS progression, we performed gene-expression analysis of syngeneic breast cancer cell lines MCF10A, DCIS.com, and MCF10CA and cross-referenced the targets with patient cohort data.
We identified ID2 as a critical gene for DCIS initiation and found that ID2 promoted DCIS formation by enhancing cancer stemness of pre-malignant cells. ID2 also plays a pivotal role in survival of the aggressive cancer cells. In addition, we identified INHBA and GJB2 as key regulators for the transition of benign DCIS to aggressive phenotype. These two genes regulate migration, colonization, and stemness of invasive cancer cells. Upregulation of ID2 and GJB2 predicts poor prognosis after breast-conserving surgery. Finally, we found a natural compound Helichrysetin as ID2 inhibitor which suppresses DCIS formation in vitro and in vivo.
Our results indicate that ID2 is a key driver of DCIS formation and therefore is considered to be a potential target for prevention of DCIS, while INHBA and GJB2 play vital roles in progression of DCIS to IDC and they may serve as potential prognosis markers.
KeywordsBreast cancer DCIS IDC Cancer prevention
Ductal carcinoma in situ
Invasive ductal carcinoma
Inhibitor of DNA binding 2
Inhibin beta A subunit
Gap junction protein beta 2
Zinc Finger E-Box Binding Homeobox
Bone Morphogenetic Protein 7
Transforming Growth Factor Beta
Twist Family BHLH Transcription Factor
The cancer genome atlas
We thank Dr. Fariba Behbod for the Sum225 cell line.
This study was funded by This work was supported by NIH grant R01CA173499, R01CA185650, and R01CA205067 to K.W, a pilot grant from Comprehensive Cancer Center of Wake Forest University to F.X. Y.L. is supported by NIH fellowship F31CA200286. The Tumor Tissue and Pathology Shared Resources, and Biostatistics/Bioinformatics Shared Resource are supported by the Comprehensive Cancer Center of Wake Forest University NCI, National Institutes of Health Grant (P30CA012197).
Compliance with ethical standards
Conflict of interest
all of the authors declare no conflict of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants by any of the authors.
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