Tumoral expression of BRCA1, Estrogen receptor alpha and ID4 protein in patients with sporadic breast cancer

Abstract

Introduction: BRCA1 expression is downregulated in a third of sporadic breast cancers (SBC). Most of the tumors in which BRCA1 function is diminished do not express estrogen receptor alpha (ER). Recent studies suggest that the inhibitor of DNA binding (ID)-4 could participate in the hormonal regulation of BRCA1 expression.Objective: To study the relationship between tumoral expression of BRCA1, ER and ID4 in SBCs.Patients and methods: Forty patients with pathologic confirmation of SBC were included in this study. The mRNA expression of BRCA1, ER and ID4, determined by reverse transcription and polymerase chain reaction (RT-PCR), was correlated with the expression of gliceraldehid-3-phosphate-dehydrogenase (GAPDH). The results were analyzed using two-sided nonparametric tests (Chi-square and Spearman's rank correlation test) with α < 0.05.Results: Most of the tumors that expressed BRCA1 mRNA were ER-positive (p < 0.0001). In addition, a positive correlation was observed between the level of expression of these mRNAs (rs = 0.75 95% CI = 0.57-0.86; p < 0.0001). An inverse association was observed between the mRNA expression of BRCA1 and ID4 (p = 0.024) and a negative correlation between their levels of expression (rs = -0.35 95% CI -0.59 a -0.04; p = 0.028). Moreover, a negative correlation was stated between the level mRNAs of ER and ID4 (rs = -0.45 95% CI -0.66 a -0.16; p = 0.0039).Discussion: In this study we demonstrate an association between the tumoral expression of BRCA1, ER and ID4 in patients with SBC. These results are in concordance with previous studies, however, to our knowledge, no other reports have described a relationship between the expression of ID4 and ER at the mRNA level in human breast cancers. These results suggest that ID4 participates in the molecular events that regulate BRCA1 and ER expression, suggesting its role as a tumor marker or potential therapeutic target.

Expression and prognostic value of Id protein family in human breast carcinoma

“…In the present study, the expression of Id-4 protein increased in breast cancer in comparison with the adjacent breast tissues, suggesting that Id-4 protein may play a positive role in carcinogenesis of human breast cancer, consistent with the study by Shan et al (20). Moreover, expression of Id-4 protein was negatively correlated with TNM stage and survival time, suggesting that decreased Id-4 expression may promote human breast cancer progression, which is different from the results in rats that Id-4 protein positively correlated with invasive ability of a mouse breast cancer cell line (21), and this result is also different from the results that Id-4 protein was a crucial gene regulating BRCA1 expression and might therefore be important for BRCA1 regulatory pathway involved in the pathogenesis of sporadic breast cancer (13,22). This illustrated that future work is required to elucidate the function of Id-4 protein in breast cancer.…”

“…Id-1 protein was highly expressed in infiltrating human breast cancer specimens with a significant correlation with tumor angiogenesis (11), while high cytoplasmic level of Id-2 reflects a favorable prognosis in patients with primary breast cancer and reduces invasiveness of breast cancer cells (12). Id-4 is highly expressed in normal human mammary epithelium and ER-negative carcinomas, but is suppressed in ER-positive breast carcinomas and preneoplastic lesions (13). Hypermethylation of Id-4, which leads to reduced gene expression, is significantly associated with the risk of regional lymph node metastasis of human breast cancer (14).…”

ID4 controls luminal lineage commitment in normal mammary epithelium and inhibits BRCA1 function in basal-like breast cancer

“…Beger and coworkers (2001) subsequently characterised the regulators of BRCA1 gene expression and identified ID4 as an upstream regulator of the BRCA1 promoter using an inverse genomics approach in luminal breast cancer cell lines. However, our research, and that from other laboratories, has shown exclusive ID4 protein expression in the ERα-negative subtypes of breast cancer, particularly BLBC where it is believed ID4 plays a crucial role in aetiology of this disease (de Candia et al 2006, Roldán et al 2006, Wen et al 2012, Best et al 2014, Junankar et al 2015. Importantly, the inhibitory effect of ID4 on BRCA1 has since been confirmed in ERα-negative breast cancer cell lines (Crippa et al 2014).…”

“…BRCA1, the breast and ovarian cancer susceptibility gene, is responsible for the majority of hereditary breast cancer cases ( (Lakhani et al 2005, Turner et al 2007) and reviewed in Mavaddat et al 2010). BRCA1 and ERα mRNA expression have been shown to correlate in sporadic breast cancers (Roldán et al 2006), while ID4 is negatively correlated to both BRCA1 and ERα (Roldán et al 2006, Thike et al 2015. This phenomenon has been suggested to occur through ERα inhibition of ID4 in a luminal breast cancer cell line (Beger et al 2001).…”

“…BRCA1 has been shown to inhibit ERα activity and activate transcription through the transcriptional regulator p300 ( (Fan et al 1999), reviewed in Mullan et al 2006). However, it is unclear how this may affect the regulation of ID4 in malignant breast tissue where ERα and BRCA1 expression is correlated (de Candia et al 2006, Roldán et al 2006. This suggests that ID4 may be exerting similar inhibitory effects on BRCA1 and ERα, and conversely that BRCA1 and ERα may demonstrate redundancy in inhibiting ID4.…”