PRL-3 engages the focal adhesion pathway in triple-negative breast cancer cells to alter actin structure and substrate adhesion properties critical for cell migration and invasion

Abstract

Triple-negative breast cancers (TNBCs) are among the most aggressive cancers characterized by a high propensity to invade, metastasize and relapse. We previously reported that the TNBC-specific inhibitor, AMPI-109, significantly impairs the ability of TNBC cells to migrate and invade by reducing levels of the metastasis-promoting phosphatase, PRL-3. Here, we examined the mechanisms by which AMPI-109 and loss of PRL-3 impede cell migration and invasion. AMPI-109 treatment or knock down of PRL-3 expression were associated with deactivation of Src and ERK signaling and concomitant downregulation of RhoA and Rac1/2/3 GTPase protein levels. These cellular changes led to rearranged filamentous actin networks necessary for cell migration and invasion. Conversely, overexpression of PRL-3 promoted TNBC cell invasion by upregulating matrix metalloproteinase 10, which resulted in increased TNBC cell adherence to, and degradation of, the major basement membrane component laminin. Our data demonstrate that PRL-3 engages the focal adhesion pathway in TNBC cells as a key mechanism for promoting TNBC cell migration and invasion. Collectively, these data suggest that blocking PRL-3 activity may be an effective method for reducing the metastatic potential of TNBC cells.

Identification of dysregulated miRNAs in triple negative breast cancer: A meta‐analysis approach

“…From the pathway enrichment analysis, pathways in cancer, regulation of actin cytoskeleton, focal adhesion, MAPK signaling pathway, endocytosis, and Wnt signaling pathway are the most significant pathways. The research done by Gari, DeGala, Ray, Lucia, and Lambert () reported that PRL‐3 is linked to the focal adhesion pathway in TNBC cells and promotes TNBC cell migration and invasion, thus blocking PRL‐3 activity might reduce the metastatic potential of TNBC cells. One of the major pathways is the Wnt signaling pathway that is reported to be associated with TNBC tumorigenesis by controlling various tumor‐associated characteristics such as migration, stemness, anchorage‐independent growth, and chemosensitivity (Xu, Prosperi, Choudhury, Olopade, & Goss, ).…”

A chemical genetics approach identifies PTP4A3 as a regulator of colon cancer cell adhesion

“…Thus, it is unsurprising that PTPs would be key participants in cancer (4). PTP4A3 is a nonclassic intracellular PTP reported to be overexpressed in many types of cancers (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Elevated PTP4A3 levels promote cellular invasion, motility, and angiogenesis (7,16,17), which are characteristics associated with highly malignant cancers.…”

“…Cell adhesion to the ECM not only prevents programmed cell death (22) but also controls a host of other cell processes, including proliferation, migration, and cell polarity (24)(25)(26)(27). Although PTP4A3 has been linked to changes in expression levels of Ezrin, integrins, and matrix metalloproteinases, the impact of this collective network alteration on the adherence and interaction with the ECM has yet to be explored in colorectal cancer (11,20,(28)(29)(30)(31).…”

Physiological and oncogenic roles of the PRL phosphatases

“…The PRLs have also been extensively linked to Src activation in many cell types [134,145,[149][150][151][152][153][154][155], but the mechanism of action on this kinase is still obscure. Liang et al proposed that elevated PRL-3 expression activates Src by reducing the mRNA translation of Csk, a negative regulator of Src, [150,156].…”

“…Many reports have shown that overexpression of MMP-2, -7, and -9, which have been implicated in tumor progression [166], positively correlate with PRL levels in various cancer cell types [102,117,148,[167][168][169][170][171][172][173]. In addition, overexpression of PRL-3 promoted triple-negative breast cancer cell invasion by upregulating MMP-10, which resulted in degradation of one of the major basement membrane component laminin [154]. An increase in PRL-3 protein levels also promoted cell membrane accumulation of MMP-14 as a result of its increased cellular trafficking, leading to more cell migration and invasion in uveal melanoma [174].…”