title: Hormone receptor-independent CXCL10 production is associated with the regulation of cellular factors linked to breast cancer progression and metastasis.
abstract: Breast cancer (BC) is a major health problem for women around the world. Although advances in the field of molecular therapy have been achieved, the successful therapeutic management of BC, particularly metastatic disease, remains a challenge for patients and clinicians. One of the areas of current investigation is the circulating tumor cells (CTCs), which have a determinant role in the development of distant metastasis. At the present, many of the available treatment strategies for metastatic disease are of limited benefit. However, the elucidation of the mechanisms of tumor progression and metastasis may help to identify key molecules/components that may function as therapeutic targets in the future. In the present study, the functional analysis of CTCs revealed their ability to grow and proliferate to form colonies. Immunofluorescence staining of the CTCs' colonies exhibits elevated expression of cell growth and survival associated proteins such as, survivin, ERK and Akt1. More importantly, the functional screening of the chemokine profile in BC patients' sera revealed an HR-independent elevation of the chemokine CXCL10 when compared to healthy controls. The analysis of chemokines CXCL9 and CXCL11 demonstrated an HR-dependent production pattern. The levels of both CXCL9 and CXCL11 were markedly high in HR+ patients' sera when compared to HR- patients and healthy controls. The functional analysis of HR+ and HR- BC derived cell lines when cultivated in media supplemented with patients' sera demonstrated the alteration of tumor progression and metastasis related proteins. We noted the induction of survivin, β-catenin, MKP-1, pERK, CXCR4 and MMP-1 both at the protein and mRNA levels. The induction of those proteins was in keeping with patients' sera induced cell proliferation as measured by the MTT assay. In conclusion, our data emphasizes the role of chemokines, especially CXCL10, in BC progression and metastasis via the induction of signaling pathways, which mainly involve survivin, β-catenin, MKP-1 and MMP-1.
authors.affiliation: Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39216, USA. Electronic address: gaidiahmed@yahoo.com.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Ejaeidi
authors.affiliation: Division of Oncology, Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Craft
authors.affiliation: Division of Oncology, Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Louis V
authors.initials: LV
authors.lastname: Puneky
authors.affiliation: Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Lewis
authors.affiliation: Department of Pathology, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Julius M
authors.initials: JM
authors.lastname: Cruse
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism*; D054371:Chemokine CXCL11 / Q000235:genetics / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000077022:Survivin; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C107489:BIRC5 protein, human; C495270:CTNNB1 protein, human; C114753:CXCL10 protein, human; C515202:CXCL11 protein, human; C515255:CXCL12 protein, human; C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; C527276:CXCR4 protein, human; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054377:Chemokine CXCL12; D054370:Chemokine CXCL9; D051034:Inhibitor of Apoptosis Proteins; D012333:RNA, Messenger; D054367:Receptors, CXCR3; D019718:Receptors, CXCR4; D000077022:Survivin; D051176:beta Catenin; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1
keywords: Breast cancer; CXCL10; CXCR3; CXCR4; Circulating tumor cells (CTCs); MMP-1; Metastasis; Survivin