Prosaposin activates the androgen receptor and potentiates resistance to endocrine treatment in breast cancer.
BACKGROUND
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.


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Endocrine Oncology Research, Department of Surgery, Royal College of Surgeons in Ireland, St. Stephens Green, Dublin 2, Ireland. azlenaali@rcsi.ie.|Department of Surgery, Beaumont Hospital, Dublin 9, Ireland. azlenaali@rcsi.ie.
Azlena
A
Ali
Endocrine Oncology Research, Department of Surgery, Royal College of Surgeons in Ireland, St. Stephens Green, Dublin 2, Ireland. lauracreevey@rcsi.ie.
Laura
L
Creevey
School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland. yhao@cshl.edu.
Yuan
Y
Hao
Endocrine Oncology Research, Department of Surgery, Royal College of Surgeons in Ireland, St. Stephens Green, Dublin 2, Ireland. damiamccartan@rcsi.ie.
Damian
D
McCartan
School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland. peadar.ogaora@ucd.ie.
Peadar
P
O'Gaora
Endocrine Oncology Research, Department of Surgery, Royal College of Surgeons in Ireland, St. Stephens Green, Dublin 2, Ireland. adkhill@rcsi.ie.|Department of Surgery, Beaumont Hospital, Dublin 9, Ireland. adkhill@rcsi.ie.
Arnold
A
Hill
Endocrine Oncology Research, Department of Surgery, Royal College of Surgeons in Ireland, St. Stephens Green, Dublin 2, Ireland. lyoung@rcsi.ie.
Leonie
L
Young
Endocrine Oncology Research, Department of Surgery, Royal College of Surgeons in Ireland, St. Stephens Green, Dublin 2, Ireland. mmcilroy@rcsi.ie.
Marie
M
McIlroy
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics*; D049231:Saposins / Q000235:genetics*; D013629:Tamoxifen / Q000494:pharmacology
C410798:AR protein, human; D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; C484731:HOXC11 protein, human; D018398:Homeodomain Proteins; C483345:PSAP protein, human; D012333:RNA, Messenger; D011944:Receptors, Androgen; D049231:Saposins; D013629:Tamoxifen