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FoxO3a Reduces Tamoxifen Resistant Breast Cancer Aggressiveness by Inducing Integrin a5 Expression
Author(s) -
Ricci Elena,
Fava Mariarosa,
Rizza Pietro,
Pellegrino Michele,
Sisci Diego,
Morelli Catia
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.05333
Subject(s) - tamoxifen , cancer research , biology , antiestrogen , breast cancer , estrogen receptor , foxo1 , transcription factor , luciferase , gene knockdown , medicine , cancer , cell culture , transfection , gene , genetics
Resistance to endocrine therapy is still a major clinical challenge in the management of estrogen receptor positive (ER+) breast cancer (BC) patients, whose poor outcome demands additional studies. Forkhead box class O (FoxO)3a transcription factor, a bona fide oncosuppressor, has been involved in BC metastasis as well as in antiestrogen resistance. Here we demonstrate that the α5 subunit of the integrin α5β1, a well‐known membrane heterodimer controlling cell surface adhesion and signaling, is a novel FoxO3a transcriptional target. FoxO3a re‐expression reduces motility (wound healing and transmigration assays) of different Tamoxifen resistant BC cell lines, through the induction of α5 mRNA (qRT‐PCR) and protein (Western blot) levels. FoxO3a transcriptionally regulates α5 expression by binding to specific Forkhead responsive elements located on the α5 promoter (Luciferase and ChIP assays). Accordingly, using a large‐scale BC gene expression datasets from The Cancer Genome Atlas (TCGA) database, a strong positive correlation between FoxO3a and α5 in ER+ BC patients emerged. Altogether, our data unveil an additional mechanism through which FoxO3a activation/induction, by increasing α5 expression, restores a less aggressive phenotype in BC refractory to endocrine therapy.