Journal of the National Cancer Institute Advance Access originally published online on May 13, 2008
JNCI Journal of the National Cancer Institute 2008 100(10):753-754; doi:10.1093/jnci/djn130
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© The Author 2008. Published by Oxford University Press.
CORRESPONDENCE |
Response: Re: Molecular Basis for Estrogen Receptor 
Deficiency in BRCA1-Linked Breast Cancer
Affiliations of authors: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK (AMH, JJG, JEQ, DPH); University College Dublin School of Medicine and Medical Science and the UCD Conway Institute of Biomolecular and Biomedical Science, Dublin, Ireland, UK (WYC, AM)
Correspondence to: D. Paul Harkin, PhD, Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK (e-mail: d.harkin{at}qub.ac.uk).
We thank Lusa et al. for their interest in our study and would like to address some of their findings. They provide data on the correlation between BRCA1 mRNA levels and estrogen receptor (ER) status as assessed by immunohistochemistry (IHC). Tumor sections were scored as ER positive if at least 10% of the tumor cells were labeled (1). They found that tumor expression of BRCA1 mRNA was weakly associated with positive ER status. IHC is not an intrinsically quantitative measure for the actual ER tumor content; therefore, we think that to obtain a more robust dataset it is necessary to quantitatively measure ER mRNA and/or protein expression levels for comparison to the measured BRCA1 mRNA levels.
Using real-time quantitative polymerase chain reaction (qPCR), Roldan et al. (2) found a positive correlation between the levels of BRCA1 and ESR1 mRNA expression in 40 sporadic breast cancers (Spearmann 
= 0.75, 95% confidence interval = 0.57 to 0.86; P < .0001). In addition, we have carried out a retrospective analysis in an independent cohort of 61 sporadic breast cancers to examine the relationship between levels of BRCA1 and ESR1 mRNA expression. In agreement with the findings of Roldan et al., our qPCR analysis revealed a statistically significant positive association between the levels of BRCA1 mRNA and ESR1 mRNA in these tumors (P < .002) (Figure 1). Other studies (3–5) have shown that reduced expression of BRCA1 (by mechanisms that include epigenetic silencing) in sporadic cancers is associated with ER negativity. It is interesting that when Lusa et al. analyzed ESR1 mRNA levels in the ER-positive samples (34 of the 50 breast tumors), they found that tumors with higher BRCA1 mRNA expression levels also had higher levels of ESR1 mRNA expression, which is consistent with our proposal (6) and the findings reported here (Figure 1).
|
Lusa et al. also examined whether specific BRCA1 gene mutations are associated with ER-positive status in a series of BRCA1-mutant tumors, of which 24 were classified as ER positive and 65 as ER negative by IHC. They found no preferential grouping of mutations according to ER status. However, they noted that of the 15 patients who carried the 5382insC mutation, 12 were ER negative and three were ER positive. This interesting finding suggests that ER-positive status in BRCA1-mutant tumors may be influenced by factors in addition to the BRCA1 gene mutation status and is in agreement with the published literature, which consistently identifies a subpopulation of BRCA1-mutant tumors that are ER positive. A concern remains, however, regarding the manner in which the studies by Lusa et al. were performed, particularly the manner in which ER positivity was determined by IHC.
We agree with Lusa et al. that mechanisms that do not involve BRCA1 expression are also likely to influence ER expression in breast tumors. Other factors that regulate ER expression may act independently of BRCA1, synergize with BRCA1, or antagonize the effect of BRCA1. Our study has illustrated one of the mechanisms of ER regulation and has brought us closer to understanding the frequently observed phenomenon of reduced ER expression in breast tumors that have lost BRCA1 function.
REFERENCES
1. Casalini P, Carcangiu ML, Tammi R, et al. Two distinct local relapse subtypes in invasive breast cancer: effect on their prognostic impact. Clin Cancer Res. (2008) 14(1):25–31.
2. Roldan G, Delgado L, Muse IM. Tumoral expression of BRCA1, estrogen receptor alpha and ID4 proteins in patients with sporadic breast cancer. Cancer Biol Ther. (2006) 5(5):505–510.[Web of Science][Medline]
3. Catteau A, Harris WH, Xu CF, Solomon E. Methylation of the BRCA1 promoter region in sporadic breast and ovarian cancer: correlation with disease characteristics. Oncogene. (1999) 18(11):1957–1965.[CrossRef][Web of Science][Medline]
4. Schmutzler RK, Bierhoff E, Werkhausen T, et al. Genomic deletions in the BRCA1, BRCA2 and TP53 regions associate with low expression of the estrogen receptor in sporadic breast carcinoma. Int J Cancer. (1997) 74(3):322–325.[CrossRef][Web of Science][Medline]
5. Birgisdottir V, Stefansson OA, Bodvarsdottir SK, Hilmarsdottir H, Jonasson JG, Eyfjord JE. Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer. Breast Cancer Res. (2006) 8(4). R38.
6. Hosey AM, Gorski JJ, Murray MM, et al. Molecular basis for estrogen receptor 
deficiency in BRCA1-linked breast cancer. J Natl Cancer Inst. (2007) 99(22):1683–1694.
Related Correspondence
CiteULike 
Connotea 
Del.icio.us What's this?
Deficiency in BRCA1-Linked Breast Cancer
J Natl Cancer Inst 2008 100: 752-753.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||