Abstract
Estrogen receptor‐alpha (ERα)‐positive breast cancer is often treated with antihormonal regimens. However, resistance to treatment is common, leading to metastatic disease. ERα activity requires the functional involvement of pioneer factors FOXA1 and GATA3, which enable ERα–chromatin binding and are crucial for ERα‐driven cell proliferation. FOXA1 was found increased in metastatic breast cancers in relation to the primary tumor, but a comprehensive clinical assessment thereof, in relation to different metastatic sites and endocrine therapy usage, is currently lacking. Prior cell line‐based reports, however, have revealed that FOXA1 is required for tamoxifen‐resistant tumor cell proliferation. We studied expression levels of ERα, GATA3, and FOXA1 by immunohistochemistry in samples from both primary tumors and various metastatic sites. For all factors, expression levels varied between the metastatic sites. For pleural metastases, strong variation was found in FOXA1 and GATA3 levels. Although GATA3 levels remained unaltered between primary breast cancer and pleural metastases, FOXA1 levels were reduced exclusively in metastases of patients who received endocrine therapies in the adjuvant setting, even though ERα was still expressed. Importantly, decreased FOXA1 levels in pleural metastases correlated with hormone irresponsiveness in the palliative setting, while no such correlation was found for GATA3. With this, we show divergent clinical correlations of the two ERα pioneer factors FOXA1 and GATA3 in metastatic breast cancer, where endocrine therapy resistance was associated with decreased FOXA1 levels in pleural metastases.
Highlights
Breast cancer is the most common malignancy in women with 1.7 million newly diagnosed cases annually worldwide and over 550 000 patients succumbing to the consequences of the disease each year (Ferlay et al, 2015)
As expected for transcription factors, clear nuclear signal intensity was observed for estrogen receptor-alpha (ERa), forkhead box protein A1 (FOXA1), and GATA binding protein 3 (GATA3) in the primary breast cancers as well as the metastatic samples (Fig. 1A)
These patterns differed between the different metastatic sites, with FOXA1 highly expressed in practically all skin and brain metastases, while GATA3 more often showed lower expression levels in brain metastases
Summary
Breast cancer is the most common malignancy in women with 1.7 million newly diagnosed cases annually worldwide and over 550 000 patients succumbing to the consequences of the disease each year (Ferlay et al, 2015). Around 70% of all breast tumors are of the luminal subtype, in which estrogen receptor-alpha (ERa) is the main driver of cell proliferation, and the prime drug target in treatment (Beelen et al, 2012; Droog et al, 2013) These patients are generally treated with endocrine therapies in the adjuvant setting: tamoxifen or aromatase inhibitors. Several intrinsic resistance mechanisms to hormonal intervention have been described, including activation of kinase pathways (Kok et al, 2011; de Leeuw et al, 2013; Zwart et al, 2007a) and overexpression of coregulators that are involved in ERa function (Zwart et al, 2007b, 2009) All these resistance mechanisms enable tumor cell proliferation despite hormonal therapy, giving rise to outgrowth of metastatic breast cancer (Kennecke et al, 2010)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
