TY - JOUR
T1 - Splicing program of human MENA produces a previously undescribed isoform associated with invasive, mesenchymal-like breast tumors
AU - Di Modugno, Francesca
AU - Iapicca, Pierluigi
AU - Boudreau, Aaron
AU - Mottolese, Marcella
AU - Terrenato, Irene
AU - Perracchio, Letizia
AU - Carstens, Russ P.
AU - Santoni, Angela
AU - Bissell, Mina J.
AU - Nisticò, Paola
PY - 2012/11/20
Y1 - 2012/11/20
N2 - 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 11ais 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 hMENA11a, overexpression of hMENAΔv6 increased cell invasion, whereas overexpression of hMENA 11a reduced the migratory and invasive ability of these cells. hMENA11a 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 hMENA11a, 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 hMENA11a. 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.
AB - 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 11ais 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 hMENA11a, overexpression of hMENAΔv6 increased cell invasion, whereas overexpression of hMENA 11a reduced the migratory and invasive ability of these cells. hMENA11a 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 hMENA11a, 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 hMENA11a. 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.
KW - EMT
KW - ENAH
KW - Splice variants
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U2 - 10.1073/pnas.1214394109
DO - 10.1073/pnas.1214394109
M3 - Article
C2 - 23129656
AN - SCOPUS:84869767975
VL - 109
SP - 19280
EP - 19285
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 47
ER -