Forkhead-box A1 (FOXA1) expression in breast cancer and its prognostic significance

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Abstract

The forkhead-box A1 (FOXA1) controls downstream transcription of oestrogen receptor (ER)-regulated genes. In this study, the biological and prognostic value of FOXA1 expression was assessed immunohistochemically in a large and well-characterised series of invasive breast carcinoma with a long term follow-up using tissue microarray. FOXA1 expression was associated with steroid hormone receptors (ERα, PgR and AR), other variables of good prognosis such as smaller tumour size, lower histological grade, luminal cytokeratins (CK18 and CK7/8), BRCA1 and E-cadherin. Its expression showed an inverse relation with basal CKs (CK14 and CK5/6) and P-cadherin. We found an association between high FOXA1 expression and a better survival in the whole series however; multivariate analysis showed that FOXA1 was not an independent prognostic marker.

In conclusion, our results show that FOXA1 protein is associated with markers of good prognosis supporting its role as a growth repressor in breast cancer. In this series, FOXA1 was found not to be of an independent prognostic significance in breast cancer and as such its immunohistochemical assessment alone does not appear to have relevance in routine practice to stratify ER-positive (luminal-like) tumours into clinically significant subgroups.

Introduction

The forkhead-box A1 (FOXA1) gene is a member of the fox family of transcription factors, expressed in the breast, liver, pancreas, bladder, prostate, colon and lung and can bind to the promoters of more than hundred genes associated with regulation of cell signalling and the cell cycle. 1, 2 It is involved in the pathogenesis of many cancers including lung and prostate cancer.2 In prostate cancer, FOXA1 plays a growth inhibitory role and its expression is associated with markers of differentiation. Previous studies have shown that FOXA1 can act either as a growth stimulator or as a repressor. As a stimulator, it functions as a pioneer factor that binds to chromatinised DNA, opens the chromatin and enhances binding of oestrogen receptor-alpha (ERα) to its target genes.3 Emphasising its importance, FOXA1 is required for the expression of 50% of ER-regulated genes.3, 4 Using an in vitro model, down-regulation of FOXA1 by RNA interference significantly suppressed proliferation of ErbB2-negative and FOXA1-positive breast cancer cell lines.5

As a repressor, it has been shown that FOXA1 overexpression can block the metastatic progression by influencing expression of the BRCA1 associated cell cycle inhibitor, p27 and promoting E-cadherin expression. This suggests that FOXA1 plays important roles in the upregulation of genes that reduce the growth and motility of breast cancer cells.6, 7

Importantly, recent global gene expression studies of breast cancer revealed that high FOXA1 mRNA expression is often found in association with ER positivity, and frequently present in a subset of ER-positive tumours that have a favourable outcome (luminal A tumours).8, 9 Therefore, FOXA1 expression appears to have potential relevance in the subclassification of luminal/ER-positive tumours into two subgroups with different biological behaviour and prognosis corresponding to the luminal A and B classes identified in gene expression profiling studies.8, 9

In this study, FOXA1 protein expression was investigated in the largest series of breast cancers examined to date (696) using high throughput tissue microarrays (TMAs) and immunohistochemistry. Clinicopathological, therapy and outcome information, as well as data on different biomarkers of strong relevance to breast cancer and to FOXA1 protein regulation were available. Data analyses were performed in order to assess the biological and clinical significance of FOXA1 protein expression in unselected primary breast cancer patients as well as in prognostically important subgroups.

Section snippets

Patient selection

Tissue microarrays (TMAs) were prepared from a series of 880 cases of primary operable breast carcinoma cases from patients age <70 presenting consecutively to the Nottingham Breast Unit, as previously reported10 This resource has been well characterised and contains patients’ clinical and pathological data including patients’ age, histological tumour type, primary tumour size, lymph node status, mitotic count and histological grade,11 Nottingham prognostic index (NPI),12 vascular invasion

Results

After excluding the uninformative TMA cores from the study, 696 tumours were available for assessment. The median age of the patients was 54 years (range 27–70). The staining pattern was nuclear with no evidence of cytoplasmic or membranous staining (Fig. 1A–C). The expression was detected in the nuclei of the malignant cells as well as in some luminal ductal epithelial cells of the entrapped normal tissues in the cores. In the whole series, 55% of the tumours showed a nuclear expression for

Discussion

In recent years, the hunt for reliable prognostic markers and response indicators to various systemic therapies in breast cancer has dramatically increased, supporting the drive to provide more personalised medicine. Several high throughput techniques including gene expression arrays and tissue microarrays have been used.10, 19 Gene expression profiling studies have classified breast cancer into at least five subtypes with distinct biological and clinical significance.8, 9, 20 One of the

Conflict of interest statement

None declared.

Acknowledgements

The authors thank Dr. Jane Starzynski, Heart of England NHS Foundation Trust, Birmingham for the HER2 immunostaining. Hany Habashy is funded by the Egyptian Cultural Bureau in London. Graham Ball is funded by the John and Lucille van Geest Foundation.

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