title: CD44 induces FOXP3 expression and is related with favorable outcome in breast carcinoma.
abstract: We studied the relationship between CD44 and Forkhead box P3 (FOXP3) gene expression in cell lines and breast carcinomas and their association with clinicopathological variables and patient outcome. We assessed messenger RNA (mRNA) expression of CD44 and FOXP3 by quantitative real-time PCR and determined the number of FOXP3+ Tregs by immunohistochemistry in 264 breast cancer specimens. CD44 was stimulated with hyaluronan treatment, and the accompanying changes in FOXP3 mRNA expression in breast cancer cell lines representing breast cancer subtype were assessed. We found that lower CD44 expression correlated with the presence of necrosis, lymph-vascular invasion, grade 3 tumors, and aggressive phenotype (HER2 and basal-like). FOXP3 mRNA correlated positively with CD44 mRNA expression and Treg content. Moreover, stimulation of CD44 expression by hyaluronan in cell lines increased FOXP3 expression, which supports that their regulation is associated. Survival analysis revealed that low CD44 expression is associated with higher frequency of recurrence. Our findings indicate that CD44 has a regulatory role in FOXP3 expression and is associated with good prognostic factors in breast cancer.
authors.affiliation: Research Unit, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), and Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), C/ Pintor Baeza 12, ZC: 03010, Alicante, Spain. sanmartin_ele@gva.es.
authors.forename: Elena
authors.initials: E
authors.lastname: Sanmartín
authors.affiliation: Research Unit, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), and Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), C/ Pintor Baeza 12, ZC: 03010, Alicante, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Ortiz-Martínez
authors.affiliation: Research Unit, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), and Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), C/ Pintor Baeza 12, ZC: 03010, Alicante, Spain.
authors.forename: Eloy
authors.initials: E
authors.lastname: Pomares-Navarro
authors.affiliation: Research Unit, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), and Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), C/ Pintor Baeza 12, ZC: 03010, Alicante, Spain.
authors.forename: Araceli
authors.initials: A
authors.lastname: García-Martínez
authors.affiliation: Research Unit, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), and Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), C/ Pintor Baeza 12, ZC: 03010, Alicante, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Rodrigo-Baños
authors.affiliation: Research Unit, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), and Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), C/ Pintor Baeza 12, ZC: 03010, Alicante, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: García-Escolano
authors.affiliation: Pathology Department, Hospital de Cruces, Plaza de Cruces n° 2, ZC: 48903, Barakaldo, Spain.
authors.forename: Leire
authors.initials: L
authors.lastname: Andrés
authors.affiliation: Pathology Department, Hospital de la Santa Creu i Sant Pau, C/ Sant Quintí 87-89, ZC: 08041, Barcelona, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Lerma
authors.affiliation: Pathology Department, University General Hospital of Alicante, C/ Pintor Baeza 12, ZC: 03010, Alicante, Spain.
authors.forename: Francisco I
authors.initials: FI
authors.lastname: Aranda
authors.affiliation: Biotechnology Department, Immunology Division, University of Alicante, ZC: 03080, Alicante, Spain.
authors.forename: Pascual
authors.initials: P
authors.lastname: Martínez-Peinado
authors.affiliation: Biotechnology Department, Immunology Division, University of Alicante, ZC: 03080, Alicante, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Sempere-Ortells
authors.affiliation: Research Unit, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), and Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), C/ Pintor Baeza 12, ZC: 03010, Alicante, Spain.|Pathology Department, University General Hospital of Alicante, C/ Pintor Baeza 12, ZC: 03010, Alicante, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Peiró
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C497483:CD44 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D018960:Hyaluronan Receptors
keywords: Breast carcinoma; CD44; FOXP3; Prognosis; mRNA expression