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Progesterone receptor B (PRB) promoter hypermethylation in sporadic breast cancer

Progesterone receptor B hypermethylation in breast cancer

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Abstract

Introduction Oestrogen receptor alpha (ER alpha) is traditionally measured on all breast tumour specimens to identify those patients more likely to respond to anti-oestrogens. Progesterone receptor (PR) status has contributed useful information in defining more responsive subgroups. PR negativity may be a marker for increased signalling through growth factor receptor tyrosine kinase pathways. Progesterone acts through two PRs, PRA and PRB. PRB, the functionally active PR, can be silenced by promoter hypermethylation. Methods Following DNA and RNA extraction from 94 breast carcinomas, the methylation status of the PRB promoter was assessed by sodium bisulphite modification and methylation sensitive PCR (MSP). A quantitative realtime PCR analysis (QRTPCR) was used to determine the levels of PRB mRNA expression. Protein expression was evaluated immunohistochemically with a commercially available PRB antibody. Results 76% of the primary breast carcinoma samples demonstrated a methylated band for PRB. PRB methylation significantly compromised total PR immunohistochemistry (IHC) expression (P = 0.03). PRB mRNA correlated positively with total PR IHC (r = 0.58, P = 0.04), ER alpha IHC (P = 0.02), and tumour grade (P = 0.01). PRB protein expression was significantly associated with a number of favourable prognostic variables including smaller (P = 0.004) lower grade (P = 0.007), ER alpha IHC positive tumours (P < 0.001), and tumours with a low Nottingham Prognostic Index (NPI) (P = 0.0008). PRB mRNA levels were significantly associated with better overall survival (P = 0.04) in a univariate analysis. Conclusion The majority of tumours were methylated for PRB. This did not directly compromise PRB expression suggesting that other factors may down regulate the PR gene. When PRB was expressed, it correlated with good prognostic markers and better overall survival.

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Acknowledgement

The present study was supported by a Mater Research Grant.

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Authors and Affiliations

  1. The Adelaide and Meath Hospital, Dublin Incorporating the National Childrens Hospital, Tallaght, Dublin, 24, Ireland

    Orla Mc Cormack

  2. UCD School of Medicine and Medical Science (SMMS), UCD Conway Institute, Belfield, Dublin 4, Ireland

    Wen Y. Chung, Fiachra Cooke, Barbara Flynn, Edward Fox, Emma Gallagher, Aloysius McGoldrick & Amanda McCann

  3. UCD School of Public Health and Population Science, Belfield, Dublin 4, Ireland

    Patricia Fitzpatrick

  4. Department of Pathology, Mater Misericordiae Hospital, Eccles St., Dublin 7, Ireland

    Michele Harrison & Peter A. Dervan

  5. Clinical Science Institute, University College Hospital, Galway, Ireland

    Michael J. Kerin

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  1. Orla Mc Cormack
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  2. Wen Y. Chung
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  3. Patricia Fitzpatrick
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  4. Fiachra Cooke
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  5. Barbara Flynn
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  6. Michele Harrison
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  7. Edward Fox
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  8. Emma Gallagher
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  9. Aloysius McGoldrick
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  10. Peter A. Dervan
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  11. Amanda McCann
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  12. Michael J. Kerin
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Correspondence to Orla Mc Cormack.

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Mc Cormack, O., Chung, W.Y., Fitzpatrick, P. et al. Progesterone receptor B (PRB) promoter hypermethylation in sporadic breast cancer. Breast Cancer Res Treat 111, 45–53 (2008). https://doi.org/10.1007/s10549-007-9757-7

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  • DOI: https://doi.org/10.1007/s10549-007-9757-7

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