Laminin signals initiate the reciprocal loop that informs breast-specific gene expression and homeostasis by activating NO, p53 and microRNAs

Abstract

How mammalian tissues maintain their architecture and tissue-specificity is poorly understood. Previously, we documented both the indispensable role of the extracellular matrix (ECM) protein, laminin-111 (LN1), in the formation of normal breast acini, and the phenotypic reversion of cancer cells to acini-like structures in 3-dimensional (3D) gels with inhibitors of oncogenic pathways. Here, we asked how laminin (LN) proteins integrate the signaling pathways necessary for morphogenesis. We report a surprising reciprocal circuitry comprising positive players: laminin-5 (LN5), nitric oxide (NO), p53, HOXD10 and three microRNAs (miRNAs) — that are involved in the formation of mammary acini in 3D. Significantly, cancer cells on either 2-dimensional (2D) or 3D and non-malignant cells on 2D plastic do not produce NO and upregulate negative players: NFκB, EIF5A2, SCA1 and MMP-9 — that disrupt the network. Introducing exogenous NO, LN5 or individual miRNAs to cancer cells reintegrates these pathways and induces phenotypic reversion in 3D. These findings uncover the essential elements of breast epithelial architecture, where the balance between positive- and negative-players leads to homeostasis.

Finding new cancer epigenetic and genetic biomarkers from cell-free DNA by combining SALP-seq and machine learning: esophageal cancer as an example

“…Furthermore, elevated expression of WHSC1 is often observed in many types of human cancers, and expression product of WHSC1 is essential for the growth of cancer cells [52][53][54] . The gene EIF5A2 was related to not only ESCA [55][56][57] , but also breast cancer 58 , lung cancer 59,60 , bladder cancer 61,62 , stomach cancer [63][64][65] , oral cancer 66 , liver cancer 67 , and colorectal cancer 68 . By checking the expression of these genes detected in tumors (RNA-seq data in TCGA), most of these genes are significantly up-regulated in tumors ( Fig.…”

An interplay between reaction-diffusion and cell-matrix adhesion regulates multiscale invasion in early breast carcinomatosis

“…Given discrete assumptions that are confirmed by experiments, the same framework could give rise to phenotypes exhibited by non-malignant, malignant but non-invasive, sub-invasive and aggressively invasive malignant cells. In case of noncancerous cells, their quiescent and lumen-containing architecture was dependent on adhesion to basement membrane matrix; inability to do so resulted in anoikis (Bissell et al, 2002; Frisch and Francis, 1994; Furuta et al, 2018; Schwartz, 1997). The model predicts that the transition from homeostatic to a precancerous carcinoma-in-situ-like (DCIS) structures involves anchorage-independent survival and division.…”

“…Three-dimensional (3D) organotypic and pathotypic cultures of cancer cell lines and primary patient cells have helped extend our understanding of the molecular mechanisms underlying cancer (Torras et al, 2018; Weinhart et al, 2019). 3D cultures are approximations of the histopathological complexity of in vivo tumor microenvironments; most current models involve embedding cancer epithelia within a natural or tunable synthetic matrix scaffolds(Balachander et al, 2015; Bhat et al, 2016; Furuta et al, 2018) (more complicated versions comprise efforts to mimic the perivascular and endothelial metastatic niches (Carlson et al, 2019; Ghajar et al, 2013) as well as efforts to engineer platforms consisting of multiple organs-on-a-chip reviewed by (Zhao et al, 2019)).…”

The network of non-coding RNAs and their molecular targets in breast cancer

“…Further considerations on opposite effects of ncRNAs could be drawn by the second cluster, where the miR-30's family members suppressed cell invasion in vitro and bone metastasis in vivo by targeting genes implicated in invasiveness (ITGA5, ITGB3) and osteo-mimicry (CDH11) in TNBC [148]. Consistently, miR-30a was involved in EMT regulation, upon TP53 stimulation, by targeting ZEB2 [149], while miR-30e displayed an onco-suppressor role through the modulation of ataxin 1 (SCA1) and EIF5A2, two disruptors of the BC acini morphogenesis promoted by laminin111 (LN1) [100]. MiR-181a could also lead to a reduction in the activation of pro-MMP-2, cell migration and invasion of BC cells through matrix-metalloproteinase MMP-14 [150].…”