Type

Journal Article

Authors

Marie McIlroy
Leonie Young
Arnold Hill
Peadar O'Gaora
Damian McCartan
Yuan Hao
Laura Creevey
Azlena Ali

Subjects

Medicine & Nursing

Topics
cell migration hormone responsive element hoxc11 gene cohort analysis in vitro study disease free survival surgery cancer cell treatment response human cancer cells cancer patient cancer incidence cancer treatment cancer cell lines phenotype cancer hormone therapy protein motif estrogen responsive element medicine and health sciences rna sequence gene targeting androgen receptor cell invasion breast cancer patients growth and development breast cancer gene

Prosaposin activates the androgen receptor and potentiates resistance to endocrine treatment in breast cancer. (2015)

Abstract HOX genes play vital roles in growth and development, however, atypical redeployment of these genes is often associated with steroidal adaptability in endocrine cancers. We previously identified HOXC11 to be an indicator of poor response to hormonal therapy in breast cancer. In this study we aimed to elucidate genes regulated by HOXC11 in the endocrine resistant setting. RNA-sequencing paired with transcription factor motif-mapping was utilised to identify putative HOXC11 target genes in endocrine resistant breast cancer. Validation and functional evaluation of the target gene, prosaposin (PSAP), was performed in a panel of endocrine sensitive and resistant breast cancer cell lines. The clinical significance of this finding was explored in clinical cohorts at both mRNA and protein level. PSAP was shown to be regulated by HOXC11 in both tamoxifen and aromatase inhibitor (AI) resistant cell lines. Transcript levels of HOXC11 and PSAP correlated strongly in samples of primary breast tumours (r = 0.7692, n = 51). PSAP has previously been reported to activate androgen receptor (AR) in prostate cancer cells. In a panel of breast cancer cell lines it was shown that endocrine resistant cells exhibit innately elevated levels of AR compared to their endocrine sensitive counterparts. Here, we demonstrate that stimulation with PSAP can drive AR recruitment to a hormone response element (HRE) in AI resistant breast cancer cells. Functionally, PSAP promotes cell migration and invasion only in AI resistant cells and not in their endocrine sensitive counterparts. In a cohort of breast cancer patients (n = 34), elevated serum levels of PSAP were found to associate significantly with poor response to endocrine treatment (p = 0.04). Meta-analysis of combined PSAP and AR mRNA are indicative of poor disease-free survival in endocrine treated breast cancer patients (hazard ratio (HR): 2.2, P = 0.0003, n = 661). The HOXC11 target gene, PSAP, is an AR activator which facilitates adaptation to a more invasive phenotype in vitro. These findings have particular relevance to the development of resistance to AI therapy which is an emerging clinical issue. PSAP is a secreted biomarker which has potential in identifying patients failing to exhibit sustained response to hormonal treatment.
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Full list of authors on original publication

Marie McIlroy, Leonie Young, Arnold Hill, Peadar O'Gaora, Damian McCartan, Yuan Hao, Laura Creevey, Azlena Ali

Experts in our system

1
Marie McIlroy
Royal College of Surgeons in Ireland
 
2
Leonie S Young
Royal College of Surgeons in Ireland
Total Publications: 42
 
3
Arnold D K Hill
Royal College of Surgeons in Ireland
Total Publications: 110
 
4
Peadar O'Gaora
University College Dublin
Total Publications: 11
 
5
Yuan Hao
Royal College of Surgeons in Ireland
Total Publications: 5