Are estrogen receptor-positive breast cancers in BRCA1 mutation carriers sporadic?

There is a strong association between BRCA1 mutation carrier status and estrogen receptor-negative breast cancer. This has led to the idea that estrogen receptor-positive breast cancers in BRCA1 mutation carriers may be incidental or sporadic in nature and not as a direct result of BRCA1 dysfunction. A recent paper in Breast Cancer Research challenges this view.

towards higher grade and mitotic activity, and were predominantly ductal carcinoma -no special type. Th is last conclusion is the most signifi cant, suggesting that ER-positive, BRCA1-associated tumors are not simply incidental. Although the data are not conclusive, they are intriguing.
Th ere are some inevitable limitations to the study. Th e number of patients analyzed is small, the pathological data in parts are incomplete, and the data on ER status are a mixture of biochemical and immunohistochemistry analyses. Th e pathologists were blinded to ER status but do not appear to have been blinded to BRCA1 status. Many of the limitations are unavoidable due to the nature of the population studied and the type of analysis attempted. However, they do limit the eventual conclusions that can be drawn.
Th ere is a clear and strong association between older age (and hence menopausal status) and the development of ER-positive breast cancers in BRCA1 mutation carriers. Although these data are consistent with those of Vaziri and colleagues [2] and Foulkes and colleagues [3], the latter study demonstrated that at every age interval, the likelihood of developing an ER-negative breast cancer for BRCA1 mutation carriers is much greater than in controls. Th ere is also clear evidence in the literature that in the general population there is an increase in ERpositive cancers with increasing age [4,5]. Collectively, this would be consistent with the hypothesis that a high proportion of ER-positive cancer in BRCA1 mutations carriers is incidental. Th e pathology data from the study, however, argue against this. Th e ER-positive breast cancers in BRCA1 mutation carriers are not only diff erent to the ER-negative cancers, they are also diff erent to sporadic ERpositive breast cancers in the general population matched for age and year of diagnosis. Th is suggests a biological eff ect, although the exact mechanism remains elusive.
Th ere are compelling data that estrogen plays a key role in the development of BRCA1-dependent breast cancers. Premenopausal oophorectomy in BRCA1 mutation carriers substantially reduces the risk of subsequent carci noma [6], as does treatment with Tamoxifen [7]. Further more, BRCA1 function is linked to ER expression

Abstract
There is a strong association between BRCA1 mutation carrier status and estrogen receptor-negative breast cancer. This has led to the idea that estrogen receptorpositive breast cancers in BRCA1 mutation carriers may be incidental or sporadic in nature and not as a direct result of BRCA1 dysfunction. A recent paper in Breast Cancer Research challenges this view. and knockdown of BRCA1 leads to loss of ER expression [8]. It is therefore confusing that some BRCA1 mutation carriers develop tumors that are ER-positive. It is not clear whether these tumors arise as a result of BRCA1 haploinsuffi ciency -additional methylation, expression and loss of heterozygosity studies are needed to address this question. Th e Consortium of Investigators of Modifi ers of BRCA1/2 is currently collecting data to stratify BRCA1-associated tumors by ER status in order to determine whether polymorphisms that alter the risk of ER-positive, but not ER-negative, unselected breast cancer also modify risk of ER-positive, but not of ERnegative, BRCA1-related breast cancer (GChenevix-Trench, personal communication).
Th e authors postulate that ER-positive and ER-negative cancers in BRCA1 mutation carriers may arise from diff erent cell populations (early progenitor cells versus stem cells). Although it is tempting to speculate on the cell of origin, especially as it has recently been suggested that BRCA1/basal breast cancers may arise from luminal progenitors [9], it is worth noting that we know little about cell plasticity in normal development or tumori genesis. It is equally plausible that a combination of age-related metabolic changes, locally within the breast and systemically, environmental exposures together with the predisposition of the cells to genomic instability as a result of BRCA1 DNA repair dysfunction could result in the same cell populations producing diff erent tumor subtypes.
An important unanswered question is whether preventive strategies in BRCA1 mutation carriers will change the age distribution and hence the subtypes of cancers seen in diagnostic practice, and how this will impact management.