Uncovering the signaling landscape controlling breast cancer cell migration identifies novel metastasis driver genes

Abstract

Ttriple-negative breast cancer (TNBC) is an aggressive and highly metastatic breast cancer subtype. Enhanced TNBC cell motility is a prerequisite of TNBC cell dissemination. Here, we apply an imaging-based RNAi phenotypic cell migration screen using two highly motile TNBC cell lines (Hs578T and MDA-MB-231) to provide a repository of signaling determinants that functionally drive TNBC cell motility. We have screened ~4,200 target genes individually and discovered 133 and 113 migratory modulators of Hs578T and MDA-MB-231, respectively, which are linked to signaling networks predictive for breast cancer progression. The splicing factors PRPF4B and BUD31 and the transcription factor BPTF are essential for cancer cell migration, amplified in human primary breast tumors and associated with metastasis-free survival. Depletion of PRPF4B , BUD31 and BPTF causes primarily down regulation of genes involved in focal adhesion and ECM-interaction pathways. PRPF4B is essential for TNBC metastasis formation in vivo, making PRPF4B a candidate for further drug development.

Towards an Integral Therapeutic Protocol for Breast Cancer Based upon the New H+-Centered Anticancer Paradigm of the Late Post-Warburg Era

“…On the contrary, antidiabetic drugs of the sulfonylurea family, known to stimulate the pancreatic secretion of INS, appear to have a negative impact on BC growth, also increasing BC risk [ 148 , 149 , 150 ]. Furthermore, the overexpression of insulin and/or the insulin growth factor 1 gene are associated with a decrease in the length of the life of women with BC, while their suppression increases life span and decreases tumorigenesis [ 28 , 103 , 142 , 143 , 145 , 146 , 147 , 151 , 152 , 153 , 154 , 155 , 156 , 157 ]. Hyperinsulinemia has also been considered an important factor in a wide array of human malignancies, while insulin inhibition has been proposed to decrease their growth [ 158 , 159 ].…”

“…The Na + /H + exchanger isoform 1 (NHE1), as a fundamental factor in the etiology and pathogenesis of BC [ 43 , 44 , 45 , 46 , 51 ], is produced by the APNH gene located on chromosome 1 p35–36, which is also related to the etiopathogenesis of different tumors [ 165 ]. Other genes have a role in BC metastasis, at least 133, as well as 113 migratory modulators of Hs578T and MDA-MB-231 cells, which predict BC progression and carry a bad prognosis [ 154 ]. Moreover, BRCA1 and BRCA2 are associated with familial breast and ovarian cancers [ 166 ].…”

Molecular Structure, Binding Affinity, and Biological Activity in the Epigenome

“…Another example, the bromodomain PHD finger transcription factor (BPTF), is a nucleosome-remodeling factor subunit protein, which functions as a transcription factor. If amplified, it is prognostic for primary breast cancer [79]. At the same time, BPTF PHD finger is a histone reader sensitive to the state of methylation of the histone tail [80], which underlines that the activity of transcription factors is modulated by PTMs.…”

Towards An Integral Therapeutic Protocol for Breast Cancer based upon the New H+-Centered Anticancer Paradigm of the Late Post-Warburg Era

“…On the contrary, antidiabetic drugs of the sulfonylurea family, known to stimulate the pancreatic secretion of INS, appear to have a negative impact on BC growth, also increasing BC risk [137][138][139]. Furthermore, the overexpression of INS and/or the IGF-1 gene are associated with a decrease in the length of life of women with BC, while their suppression increases life span and decreases tumorigenesis [27,91,131,132,[134][135][136][140][141][142][143][144][145][146]. Hyperinsulinemia has also been considered an important factor in a wide array of human malignancies, while insulin inhibition has been proposed to decrease their growth [147,148].…”