CITED2 in breast carcinoma as a potent prognostic predictor associated with proliferation, migration and chemoresistance

Abstract

CITED2 (Cbp/p300‐interacting transactivator, with Glu/Asp‐rich carboxy‐terminal domain, 2) is a member of the CITED family and is involved in various cellular functions during development and differentiation. Mounting evidence suggests the importance of CITED in the progression of human malignancies, but the significance of CITED2 protein has not yet been examined in breast carcinoma. Therefore, in the present study, we examined the clinical significance and the biological functions of CITED2 in breast carcinoma by immunohistochemistry and in vitro study. CITED2 immunoreactivity was detected in breast carcinoma tissues, and it was significantly higher compared to those in morphologically normal mammary glands. CITED2 immunoreactivity was significantly associated with stage, pathological T factor, lymph node metastasis, histological grade, HER2 and Ki‐67, and inversely correlated with estrogen receptor. Moreover, the immunohistochemical CITED2 status was significantly associated with increased incidence of recurrence and breast cancer‐specific death of the breast cancer patients, and multivariate analyses demonstrated CITED2 status as an independent worse prognostic factor for disease‐free and breast cancer‐specific survival. Subsequent in vitro experiments showed that CITED2 expression significantly increased proliferation activity and migration property in MCF‐7and S KBR‐3 breast carcinoma cells. Moreover, CITED2 caused chemoresistance to epirubicin and 5‐fluorouracil, but not paclitaxel, in these cells, and it inhibited p53 accumulation after 5‐fluorouracil treatment in MCF‐7 cells. These results suggest that CITED2 plays important roles in the progression and chemoresistance of breast carcinoma and that CITED2 status is a potent prognostic factor in breast cancer patients.

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“…CITED2 is a transcriptional co-regulator that directly interacts with host of transcription factors and co-activators, and influences the activation of gene transcription [ 35 , 36 ]. CITED2 is a potent prognostic predictor and associated with proliferation, migration and chemoresistance in breast cancer [ 37 ]. Moreover, CITED2 serves as a coactivator of hepatocyte nuclear factor 4α (HNF4α) in liver development [ 38 ].…”

CDK7 Inhibition Is Effective in all the Subtypes of Breast Cancer: Determinants of Response and Synergy with EGFR Inhibition

“…We were particularly interested in the finding that THZ1 inhibited CITED2 expression as this gene, not previously associated with CDK7, showed one of the strongest associations with THZ1 sensitivity. CITED2 (CBP/p300-interacting trans-activator with Glu/Asp-rich carboxy-terminal domain-2) is a non-DNA binding transcriptional co-regulator that modulates the activity of multiple transcription factors including p300/CBP, Smad2/3 and estrogen receptor [32][33][34] CITED2 is overexpressed in breast cancer compared to normal mammary tissue and CITED2 was significantly associated with increased incidence of recurrence and breast cancer-specific death of the breast cancer patients [23]. High CITED2 mRNA expression was associated with poor survival in ER positive breast cancer patients [35] and may contribute to anti-estrogen resistance [36].…”

“…High CITED2 mRNA expression was associated with poor survival in ER positive breast cancer patients [35] and may contribute to anti-estrogen resistance [36]. CITED2 promotes proliferation, migration and resistance to chemotherapy in breast cancer [23]. In addition to finding that THZ1 significantly decreased the expression of CITED2 and that the fold change in CITED2 in response to THZ1 treatment was positively correlated with the sensitivity of the cells to THZ1, we found a significant correlation between the basal protein levels of CITED2 in the panel of cells and sensitivity to THZ1.…”

“…Transcriptional co-regulator CITED2 has recently been reported as a prognostic factor in breast cancer patients with important roles in cancer progression, chemoresistance and metastasis [22,23]. Therefore, we examined in more detail the association of CITED2 with response to CDK7 inhibition.…”

Estudo funcional dos microRNAs miR-450a e miR-450b-5p na tumorigênese

“…Além disso, foi verificado que a inibição deste gene leva à maior sensibilidade à cisplatina nas linhagens A2780 e SKOV-3, efeito que pode estar associado à sua participação na sulfonação de endo e xenobióticos (LEUNG; BACKSTROM; BALLY, 2016). O gene CITED2, validado como alvo do miR-450a na linhagem A2780, participa de vários processos durante o desenvolvimento e diferenciação e leva ao aumento da taxa de proliferação, migração e resistência a quimioterápicos em carcinoma de mama (MINEMURA et al, 2016). Além disso, de acordo com dados do TCGA encontrados na base de dados "The human protein atlas" ("Expression of CITED2 in ovarian cancer -The Human Protein Atlas", [s.d.…”