CD151 represses mammary gland development by maintaining the niches of progenitor cells

Abstract

Tetraspanin CD151 interacts with laminin-binding integrins (i.e., a3b1, a6b1 and a6b4) and other cell surface molecules to control diverse cellular and physiological processes, ranging from cell adhesion, migration and survival to tissue architecture and homeostasis. Here, we report a novel role of CD151 in maintaining the branching morphogenesis and activity of progenitor cells during the pubertal development of mammary glands. In contrast to the disruption of laminin-binding integrins, CD151 removal in mice enhanced the tertiary branching in mammary glands by 2.4-fold and the number of terminal end buds (TEBs) by 30%, while having minimal influence on either primary or secondary ductal branching. Consistent with these morphological changes are the skewed distribution of basal/ myoepithelial cells and a 3.2-fold increase in proliferating Ki67-positive cells. These novel observations suggest that CD151 impacts the branching morphogenesis of mammary glands by upregulating the activities of bipotent progenitor cells. Indeed, our subsequent analyses indicate that upon CD151 removal the proportion of CD24 Hi CD49f Low progenitor cells in the mammary gland increased by 34%, and their proliferating and differentiating activities were significantly upregulated. Importantly, fibronectin, a pro-branching extracellular matrix (ECM) protein deposited underlying mammary epithelial or progenitor cells, increased by >7.2-fold. Moreover, there was a concomitant increase in the expression and nuclear distribution of Slug, a transcription factor implicated in the maintenance of mammary progenitor cell activities. Taken together, our studies demonstrate that integrin-associated CD151 represses mammary branching morphogenesis by controlling progenitor cell activities, ECM integrity and transcription program.

Regulation of Glioblastoma Tumor-Propagating Cells by the Integrin Partner Tetraspanin CD151

“…These findings demonstrate a strong mechanistic link between CD151 expression and GSC stemness and provide a novel functional context to our recent report showing that CD151 resides within a transcriptional network that is repressed by KLF9, a transcription factor that induces GSC differentiation and inhibits GSC tumor-propagating potential. Our data extend and provide a functional context to previous studies from other investigators in different organ systems showing an association of CD151 expression with the capacity of prostate cancer cells to self-renew as spheres [39] and the CD151-dependent regulation of progenitor cell pools during mammary development [58] .…”

“…A role for CD151 in regulating cell stemness and cancer stem cells remains undefined. Yin et al [58] found that CD151 knockout increased the differentiation potential of mammary luminal stem and progenitor cell subtypes, suggesting a role in modulating mammary cell multipotency and differentiation signals. We recently reported a potentially related finding that CD151 is among a network of genes that are repressed by KLF9, a transcription factor that drives GSC differentiation [27] , [59] .…”

Dub3 inhibition suppresses breast cancer invasion and metastasis by promoting Snail1 degradation

“…5b ). To corroborate these findings, we also used a second set of breast CSC markers (CD49f high /CD24 low ) 39 40 41 42 . Similar to the results presented above, Dub3 knockdown reduced the population of CD49f high /CD24 low cells in MDA-MB231 and MDA-MB157 cells (lower panel in Fig.…”

CD151-α3β1 integrin complexes are prognostic markers of glioblastoma and cooperate with EGFR to drive tumor cell motility and invasion

“…Of note, CD151 may also drive glioblastoma malignancy by affecting the stemness property of glioma cells. This tetraspanin has recently been linked to the dynamics of tumor-initiating or progenitors cells [ 43 , 44 ]. Also, CD151-associated α3 and α6 integrins are shown to enhance the aggressive behaviors of cancer stem cells [ 7 , 10 ].…”