Mena invasive (MenaINV) and Mena11a isoforms play distinct roles in breast cancer cell cohesion and association with TMEM

Roussos, Evanthia T.; Goswami, Sumanta; Balsamo, Michele; Wang, Yarong; Stobezki, Robert; Adler, Esther; Robinson, Brian D.; Jones, Joan G.; Gertler, Frank B.; Condeelis, John S.; Oktay, Maja H.

doi:10.1007/s10585-011-9388-6

Cited by 69 publications

(134 citation statements)

References 32 publications

Supporting

Mentioning

119

Contrasting

Unclassified

Order By: Relevance

“…In a xenograft rodent mammary cancer model, the invasive cancer cells showed a decrease of Mena 11a and an increase of Mena INV isoform expression (11), reminiscent of our data. The MENA INV isoform, which has an exon next to the Ena/VASP homology 1 (EVH1) domain, facilitates cell invasion by stabilizing invadopodia (12) and promoting discohesive tumor morphology, whereas MENA 11a expression appears to promote epithelial tumor morphology (30). hMENA 11a , unlike hMENA, is phosphorylated following activation of the EGFR or its other family members, suggesting that exon 11a may represent a site for regulation of hMENA 11a in breast cancer (9).…”

Section: Discussionmentioning

confidence: 99%

Splicing program of human MENA produces a previously undescribed isoform associated with invasive, mesenchymal-like breast tumors

Modugno¹,

Iapicca²,

Boudreau

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

108

146

View full text Add to dashboard Cite

Human mena (hMENA), a member of the actin cytoskeleton regulators Ena/VASP, is overexpressed in high-risk preneoplastic lesions and in primary breast tumors and has been identified as playing a role in invasiveness and poor prognosis in breast cancers that express HER2. Here we identify a unique isoform, hMENAΔv6, derived from the hMENA alternative splicing program. In an isogenic model of human breast cancer progression, we show that hMENA 11a is expressed in premalignant cells, whereas hMENAΔv6 expression is restricted to invasive cancer cells. "Reversion" of the malignant phenotype leads to concurrent down-regulation of all hMENA isoforms. In breast cancer cell lines, isoform-specific hMENA overexpression or knockdown revealed that in the absence of hMENA 11a , overexpression of hMENAΔv6 increased cell invasion, whereas overexpression of hMENA 11a reduced the migratory and invasive ability of these cells. hMENA 11a splicing was shown to be dependent on the epithelial regulator of splicing 1 (ESRP1), and forced expression of ESRP1 in invasive mesenchymal breast cancer cells caused a phenotypic switch reminiscent of a mesenchymal-to-epithelial transition (MET) characterized by changes in the cytoskeletal architecture, reexpression of hMENA 11a, and a reduction in cell invasion. hMENA-positive primary breast tumors, which are hMENA 11a -negative, are more frequently E-cadherin low in comparison with tumors expressing hMENA 11a . These data suggest that polarized and growth-arrested cellular architecture correlates with absence of alternative hMENA isoform expression, and that the hMENA splicing program is relevant to malignant progression in invasive disease.ENA along with VASP and EVL comprise the Ena/VASP family of actin regulatory proteins, which modulate cell adhesion and migration by antagonizing actin capping proteins (1, 2), bundling actin filaments, and nucleating and extending filopodia (1-7). The MENA gene encodes the 570-aa hMENA protein and different alternative splicing-derived isoforms, often expressed in a tissue-specific manner, have been reported in human (8, 9) and mouse (1, 10, 11). The neuronal variant is characterized by an extended exon 6 (1, 8), the spleen-specific variant lacks the proline-rich region (10), and an invasion-specific splice variant (MENA INV ), with an additional exon just after the EVH1 domain, has been shown to regulate chemotaxis in mouse and rat mammary tumor cells (12). Previously, we characterized hMENA 11a , an epithelial-associated hMENA splice variant with an additional exon (exon 11a) (9). hMENA 11a , expressed in human pancreatic (13) and breast cancer cells (9), is phosphorylated downstream of HER2 and EGFR following EGF and NRG1 treatment and in turn influences the mitogenic signals of these receptors in luminal breast cancer cell lines (9,14).hMENA isoforms, undetectable in normal breast tissue, are progressively expressed in premalignant breast lesions, suggesting that their presence could be used as an early stage marker of breast neoplasia in women at a hig...

show abstract

Section: Discussionmentioning

confidence: 99%

Splicing program of human MENA produces a previously undescribed isoform associated with invasive, mesenchymal-like breast tumors

Modugno¹,

Iapicca²,

Boudreau

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

108

146

View full text Add to dashboard Cite

show abstract

“…These AUC values, where 0.8 is good, 0.7 is fair and 0.6 is poor discrimination (Metz, 1978), indicate that TMEM composite is better at predicting metastasis than these other prognostics (Harney et al, 2015;Oktay and Jones, 2015;Pignatelli et al, 2014;Robinson et al, 2009;Rohan et al, 2014;Roussos et al, 2011c;Wyckoff et al, 2007). Previous reports on cancer angiogenesis and vasculogenesis have collectively demonstrated that newly constructed endothelia are composed of myeloid precursors expressing the receptor tyrosine kinase Tie2 (also known as TEK) (Riabov et al, 2014;Squadrito and De Palma, 2011), and, more recently, the mannose-receptor c-type 1 (MRC1) (Hughes et al, 2015a).…”

Section: Molecular Profiling Of Metastatic Breast Cancer Cell Subpopumentioning

confidence: 93%

Signatures of breast cancer metastasis at a glance

Karagiannis

Goswami

Jones

et al. 2016

Journal of Cell Science

Self Cite

View full text Add to dashboard Cite

Gene expression profiling has yielded expression signatures from which prognostic tests can be derived to facilitate clinical decision making in breast cancer patients. Some of these signatures are based on profiling of whole tumor tissue (tissue signatures), which includes all tumor and stromal cells. Prognostic markers have also been derived from the profiling of metastasizing tumor cells, including circulating tumor cells (CTCs) and migratory–disseminating tumor cells within the primary tumor. The metastasis signatures based on CTCs and migratory–disseminating tumor cells have greater potential for unraveling cell biology insights and mechanistic underpinnings of tumor cell dissemination and metastasis. Of clinical interest is the promise that stratification of patients into high or low metastatic risk, as well as assessing the need for cytotoxic therapy, might be improved if prognostics derived from these two types of signatures are used in a combined way. The aim of this Cell Science at a Glance article and accompanying poster is to navigate through both types of signatures and their derived prognostics, as well as to highlight biological insights and clinical applications that could be derived from them, especially when they are used in combination.

show abstract

“…Recently a splice variant of Mena, termed MenaINV, was found to be overexpressed in breast and colorectal cancers (Di Modugno et al, 2004). Mena deficiency decreases invasion, metastasis and tumour progression in polyoma middle-T transgenic mouse models and impairs normal breast development (Roussos et al, 2011a;Roussos et al, 2010;Roussos et al, 2011c).…”

Section: Filopodiummentioning

confidence: 99%