ABSTRACT
AIMS: The amplified in breast cancer 1 (AIB1), steroid receptor co-activator family member, acts as an oestrogen receptor (ER) co-activator. Acting with HER-2, it is thought to play a role in endocrine resistance by facilitating ER-growth factor crosstalk. The aim was to analyse AIB1 expression by immunohistochemistry and study its correlations with other prognostic variables in breast cancer and its effect on survival. METHODS: A tissue microarray comprising tumours from 438 patients with 15.4 years' median follow-up was used. Interpretable AIB1 expression obtained in 395 patients was analysed along with other prognostic factors in breast cancer. RESULTS: AIB1 expression scores ranged from 0 to 30; positive AIB1 expression (score > 14) was seen in 146/395 breast cancers; it correlated negatively with ER (P = 0.003) and progesterone receptor (PR) (P = 0.007), and positively with HER-2 (P = 0.005) and tumour grade (P = 0.014). It did not correlate with nodal status (P = 0.437). Among ER+ patients, AIB1 expression showed a trend towards loss of PR expression (29% versus 20%; P = 0.14). AIB1 did not predict survival on univariate or multivariate analysis. CONCLUSIONS: AIB1 expression correlates with HER-2 expression in breast cancer and shows a trend of association with loss of PR expression in ER+ tumours. Our study supports the postulated role of AIB1 in ER-growth factor interactions.
Subject(s)
Breast Neoplasms/metabolism , Histone Acetyltransferases/metabolism , Trans-Activators/metabolism , Adult , Aged , Aged, 80 and over , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Female , Follow-Up Studies , Humans , Immunohistochemistry , Middle Aged , Nuclear Receptor Coactivator 3 , Survival AnalysisABSTRACT
AIMS: Forkhead box A1 (FOXA1) is a forkhead family transcription factor expressed in breast cancer cells. It is essential for optimal expression of approximately 50% of oestrogen receptor (ER)-related genes. This study explored the FOXA1 relationship with luminal and basal breast cancer subtypes, proliferation markers, and survival in breast cancer patients who had received similar treatment. METHODS: A tissue microarray comprising tumours from 245 invasive breast cancer patients with 67 months of median follow-up was analysed for FOXA1 expression by immunohistochemistry. Interpretable FOXA1 expression, obtained in 184 patients, was analysed along with other variables such as tumour grade, size, nodal status, ER, progesterone receptor, HER2/neu, proliferation and basal markers. RESULTS: FOXA1 expression (score >3) was seen in 139 of 184 breast cancers. It correlated positively with ERalpha (p<0.0001), progesterone receptor (p<0.0001), and luminal subtype (p<0.0001); negatively with basal subtype (p<0.0001), proliferation markers and high histological grade (p = 0.0327). Univariate analysis showed nodal status, tumour grade, ER, progesterone receptor, FOXA1, basal markers and p53 as significant predictors of overall survival. Multivariate analysis showed that only nodal status (p = 0.0006) and ER (p = 0.0017) were significant predictors of OS. In luminal subtype patient subgroup, FOXA1 expression was associated with better survival (p = 0.0284) on univariate analysis. CONCLUSION: Based on this study in patients treated with surgery followed by adjuvant anthracycline-based chemotherapy, FOXA1 expression is associated with good prognosis. It correlates with luminal subtype breast cancer, and could possibly serve as a clinical marker for luminal subtype A. Prognostic ability of FOXA1 in these low-risk breast cancers may prove to be useful in treatment decision making.
Subject(s)
Biomarkers, Tumor/analysis , Breast Neoplasms/genetics , Carcinoma, Ductal, Breast/genetics , Carcinoma, Lobular/genetics , Hepatocyte Nuclear Factor 3-alpha/analysis , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/mortality , Carcinoma, Ductal, Breast/pathology , Carcinoma, Lobular/mortality , Carcinoma, Lobular/pathology , Estrogen Receptor alpha/genetics , Female , Follow-Up Studies , Gene Expression Profiling , Humans , Immunohistochemistry , Multivariate Analysis , Neoplasm Invasiveness , Neoplasm Staging , Oligonucleotide Array Sequence Analysis , Prognosis , Receptors, Progesterone/genetics , Survival AnalysisABSTRACT
The transcription factor nuclear factor kappa B (NF-kappaB) is constitutively active in both cancer cells and stromal cells of breast cancer; however, the precise role of activated NF-kappaB in cancer progression is not known. Using parental MCF10A cells and a variant that expresses the myoepithelial marker p63 stably overexpressing the constitutively active p65 subunit of NF-kappaB (MCF10A/p65), we show that NF-kappaB suppresses the expression of epithelial specific genes E-cadherin and desmoplakin and induces the expression of the mesenchymal specific gene vimentin. P65 also suppressed the expression of p63 and the putative breast epithelial progenitor marker cytokeratin 5/6. MCF10A/p65 cells were phenotypically similar to cells undergoing epithelial to mesenchymal transition (EMT). MCF10A/p65 cells failed to form characteristic acini in three-dimensional Matrigel. Analysis of parental and MCF10A/p65 cells for genes previously shown to be involved in EMT revealed elevated expression of ZEB-1 and ZEB-2 in MCF10A/p65 cells compared to parental cells. In transient transfection assays, p65 increased ZEB-1 promoter activity. Furthermore, MCF10A cells overexpressing ZEB-1 showed reduced E-cadherin and p63 expression and displayed an EMT phenotype. The siRNA against ZEB-1 or ZEB-2 reduced the number of viable MCF10A/p65 but not parental cells, suggesting the dependence of MCF10A/p65 cells to ZEB-1 and ZEB-2 for cell cycle progression or survival. MCF10A cells chronically exposed to tumor necrosis factor alpha (TNFalpha), a potent NF-kappaB inducer, also exhibited the EMT-like phenotype and ZEB-1/ZEB-2 induction, both of which were reversed following TNFalpha withdrawal.
