BMC Cancer 2008, 8:130 http://www.biomedcentral.com/1471-2407/8/130 have a high Gail risk score for cancer), but that estrone sul- phate levels were positively associated with ER labeling. The PR gene is responsive to estrogen [3] and PR levels could be considered an indicator of the current activity of estrogens in the breast tissue – a concatenation of the lev- els of ER and estrogen. Few studies have examined the association between PR levels in nonneoplastic tissue and breast cancer risk. Whereas the early study by Netto et al. [10] found that cases had a higher distribution of PR than reduction mammoplasty controls, Khan et al. [4] found no significant difference between cases and controls with respect to the mean proportion of nonneoplastic cells staining for PR. We have found a reduced risk of breast cancer associated with PR levels in nonneoplastic tissue in only one study site. We had also hypothesized that women who had higher levels of PR may be at greater risk of breast cancer due to ER levels than women who had lower levels of PR because they may be the women whose breast tissues have higher exposure to estrogen. We only found a qualitative indication of this in one of our study sites; this finding, however, was not statistically signifi- cant, could be due to chance, and should be investigated in other studies. Another analysis that we performed sup- ports this idea – the correlation between ER and PR in nonneoplastic tissue was higher in cases than controls at both sites. This suggests that for a given level of ER, the background of estrogen elicited a response, PR expression, to a greater extent in the cases than the controls. This could be due to a higher estrogen background in the cases than in the controls, or that cases have disregulated down- regulation of the ER with the estrogen-dependent expres- sion of PR. In this study and others, steroid hormone receptors may have been different between cases and controls because they could be affected by a paracrine effect from adjacent tumors or pathologies. For example, cases could have a higher level of background estrogen around the tissue in the slides used in this study because tumor tissue is known to express estrone sulphatase, 17β-hydroxysteroid dehy- drogenase, and aromatase, enzymes involved in estrogen biosynthesis [23]. Some studies have observed that the levels of aromatase and estrone sulphatase are higher in ER+/PR+ tumors than in ER-/PR- tumors [24,25], suggest- ing that the surrounding tissues of these tumors should differ in their ER and PR levels; this was not observed in this study but it has been in other studies [26,26-28]. The levels of enzymes involved in estrogen synthesis are also increased in benign breast conditions such as fibroadeno- mas [29]. Ideally, a study should be done in which steroid receptors were measured before the development of can- cer. Our study had some limitations in addition to the differ- ences in ER levels by study site. Out of necessity, our con- trols were women who had a biopsy because they were suspected of harbouring a breast tumor; many had some form of benign breast changes on this biopsy but exclu- sion of those with a lesion associated with a much higher risk of breast cancer did not change conclusions from these results. We had a small sample size that reduced the power of subgroup analyses of interest (eg. by menopau- sal status). Steroid receptor expression and other features such as extent of differentiation and involution vary by the location of the epithelial cells (eg. duct versus lobule and from lobe to lobe) [14]; ER levels, however, have been shown to be quite consistent over time [30]. Meas- urement of other factors such as proliferation, age-related involution, ER-β, PR-A and PR-B separately, and coexpres- sion of these factors may give a more complete picture of what makes the breast tissues of some women more sus- ceptible to carcinogenesis than the tissues of other women. Conclusion The results of this study and others are not inconsistent with a small increase in risk of breast cancer associated with ER levels in nonneoplastic tissue. Further work on the meaning of the role of ER-expressing cells in the breast combined with an attempt to control for the level of estro- gens to which the cells were exposed when sampled will help to clarify this question. Competing interests The authors declare that they have no competing interests. Authors' contributions CGW, SKS, WMH, and KJA contributed to the study design, the preparation of the proposal for funding, inter- pretation of the results, and the editing of the manuscript. SKS scored the immunohistochemical staining expression in all slides. CGW conducted the data analyses and pre- pared the manuscript. All authors read and approved the final manuscript. Acknowledgements The case-control study was supported by the Canadian Breast Cancer Research Initiative following a pilot study funded by Health Canada. CGW was supported in her graduate studies, during which this paper was written, by a National Cancer Institute of Canada/Canadian Cancer Society Student- ship and an Honorary Killam Memorial Studentship. KJA was supported by a Career Scientist Award from the Ontario Ministry of Health. The authors would like to thank all the subjects who participated. We also thank Shelly Hilditch, Catherine Elliott, and Deborah Gibson for their skill as project coordinators. References 1. Yager JD, Davidson NE: Estrogen carcinogenesis in breast can- cer. N Engl J Med 2006, 354:270-282. Page 8 of 9 (page number not for citation purposes)