Seyed-Mohammad Mazloomi1, Mitra Foroutan-Ghaznavi2,3,4, Vahid Montazeri5, Gholamreza Tavoosidana6, Ashraf Fakhrjou7, Hojjatollah Nozad-Charoudeh4, Saeed Pirouzpanah8,9,10. 1. Nutrition Research Center, Department of Food Hygiene and Quality Control, Faculty of Nutrition and Food Sciences, Shiraz University of Medical Sciences, Shiraz, 7193635899, Iran. 2. Students' Research Committee, Faculty of Nutrition and Food Sciences, Shiraz University of Medical Sciences, Shiraz, 7134814336, Iran. 3. Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, 5166414766, Iran. 4. Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, 5166614756, Iran. 5. Department of Thoracic Surgery, Faculty of Medicine, Tabriz University of Medical Sciences, Surgery Ward, Nour-Nejat Hospital, Tabriz, 5166614766, Iran. 6. Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, 1417755469, Iran. 7. Department of Pathology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, 5166614766, Iran. 8. Molecular Medicine Research Center, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, 5166414766, Iran. pirouzpanah@gmail.com. 9. Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, 5166614756, Iran. pirouzpanah@gmail.com. 10. Department of Biochemistry and Dietetics, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, 5166614711, Iran. pirouzpanah@gmail.com.
Abstract
BACKGROUND: Metastasis accounts for ninety percent of breast cancer (BrCa) mortality. Cortactin, Ras homologous gene family member A (RhoA), and Rho-associated kinase (ROCK) raise cellular motility in favor of metastasis. Claudins (CLDN) belong to tight junction integrity and are dysregulated in BrCa. Thus far, epidemiologic evidence regarding the association of different pro-metastatic genes with pathological phenotypes of BrCa is largely inconsistent. This study aimed to determine the possible transcriptional models of pro-metastatic genes incorporate in holding the integrity of epithelial cell-cell junctions (CTTN, RhoA, ROCK, CLDN-1, CLDN-2, and CLDN-4), for the first time, in association with clinicopathological features of primary BrCa. METHODS: In a consecutive case-series design, 206 newly diagnosed non-metastatic eligible BrCa patients with histopathological confirmation (30-65 years) were recruited in Tabriz, Iran (2015-2017). Real-time RT-PCR was used. Then fold changes in the expression of target genes were measured. RESULTS: ROCK amplification was associated with the involvement of axillary lymph node metastasis (ALNM; ORadj. = 3.05, 95%CI 1.01-9.18). Consistently, inter-correlations of CTTN-ROCK (β = 0.226, P < 0.05) and RhoA-ROCK (β = 0.311, P < 0.01) were determined among patients diagnosed with ALNM+ BrCa. In addition, the overexpression of CLDN-4 was frequently observed in tumors identified by ALNM+ or grade III (P < 0.05). The overexpression of CTTN, CLDN-1, and CLDN-4 genes was correlated positively with the extent of tumor size. CTTN overexpression was associated with the increased chance of luminal-A positivity vs. non-luminal-A (ORadj. = 1.96, 95%CI 1.02-3.77). ROCK was also expressed in luminal-B BrCa tumors (P < 0.05). The estrogen receptor-dependent transcriptions were extended to the inter-correlations of RhoA-ROCK (β = 0.280, P < 0.01), ROCK-CLDN-2 (β = 0.267, P < 0.05), and CLDN-1-CLDN-4 (β = 0.451, P < 0.001). CONCLUSIONS: For the first time, our findings suggested that the inter-correlations of CTTN-ROCK and RhoA-ROCK were significant transcriptional profiles determined in association with ALNM involvement; therefore the overexpression of ROCK may serve as a potential molecular marker for lymphatic metastasis. The provided binary transcriptional profiles need more approvals in different clinical features of BrCa metastasis.
BACKGROUND: Metastasis accounts for ninety percent of breast cancer (BrCa) mortality. Cortactin, Ras homologous gene family member A (RhoA), and Rho-associated kinase (ROCK) raise cellular motility in favor of metastasis. Claudins (CLDN) belong to tight junction integrity and are dysregulated in BrCa. Thus far, epidemiologic evidence regarding the association of different pro-metastatic genes with pathological phenotypes of BrCa is largely inconsistent. This study aimed to determine the possible transcriptional models of pro-metastatic genes incorporate in holding the integrity of epithelial cell-cell junctions (CTTN, RhoA, ROCK, CLDN-1, CLDN-2, and CLDN-4), for the first time, in association with clinicopathological features of primary BrCa. METHODS: In a consecutive case-series design, 206 newly diagnosed non-metastatic eligible BrCapatients with histopathological confirmation (30-65 years) were recruited in Tabriz, Iran (2015-2017). Real-time RT-PCR was used. Then fold changes in the expression of target genes were measured. RESULTS: ROCK amplification was associated with the involvement of axillary lymph node metastasis (ALNM; ORadj. = 3.05, 95%CI 1.01-9.18). Consistently, inter-correlations of CTTN-ROCK (β = 0.226, P < 0.05) and RhoA-ROCK (β = 0.311, P < 0.01) were determined among patients diagnosed with ALNM+BrCa. In addition, the overexpression of CLDN-4 was frequently observed in tumors identified by ALNM+ or grade III (P < 0.05). The overexpression of CTTN, CLDN-1, and CLDN-4 genes was correlated positively with the extent of tumor size. CTTN overexpression was associated with the increased chance of luminal-A positivity vs. non-luminal-A (ORadj. = 1.96, 95%CI 1.02-3.77). ROCK was also expressed in luminal-B BrCa tumors (P < 0.05). The estrogen receptor-dependent transcriptions were extended to the inter-correlations of RhoA-ROCK (β = 0.280, P < 0.01), ROCK-CLDN-2 (β = 0.267, P < 0.05), and CLDN-1-CLDN-4 (β = 0.451, P < 0.001). CONCLUSIONS: For the first time, our findings suggested that the inter-correlations of CTTN-ROCK and RhoA-ROCK were significant transcriptional profiles determined in association with ALNM involvement; therefore the overexpression of ROCK may serve as a potential molecular marker for lymphatic metastasis. The provided binary transcriptional profiles need more approvals in different clinical features of BrCa metastasis.
Entities:
Keywords:
Breast cancer; Claudin; Cortactin; Lymph node; Metastasis; ROCK; RhoA
Authors: Freddie Bray; Jacques Ferlay; Isabelle Soerjomataram; Rebecca L Siegel; Lindsey A Torre; Ahmedin Jemal Journal: CA Cancer J Clin Date: 2018-09-12 Impact factor: 508.702