BRCA2 Mutation Carriers, Reproductive Factors and Breast Cancer Risk

Laufey Tryggvadottir, Elinborg J Olafsdottir, Sigfridur Gudlaugsdottir, Steinunn Thorlacius, Jon G Jonasson, Hrafn Tulinius, Jorunn E Eyfjord

Disclosures

Breast Cancer Res. 2003;5(5) 

In This Article

Discussion

The results indicate that there are differences between carriers and noncarriers of a detrimental mutation in the BRCA2 gene with respect to the association between breast cancer risk and the number of pregnancies and between breast cancer risk and the total duration of breast feeding. No difference was detected with respect to age at menarche and to age at first birth.

Only relatively few studies published to date have addressed the effects of breast cancer risk factors on BRCA mutation carriers [7,16,17,18,19,35,36,37,38,39]. The majority of these have indicated that mutation carriers respond in a special way to breast cancer risk factors. Johannsson and colleagues[19] found an increased risk of pregnancy-associated breast cancer in carriers of BRCA1 mutations, and a weaker risk in carriers of BRCA2 mutations. Jernstrom and colleagues[16] found indications that BRCA1 mutation carriers were more likely to have problems with breast feeding than expected. Jernstrom and colleagues also reported[38] a positive association between breast cancer risk and an increasing number of births in BRCA1 and BRCA2 mutation carriers. This could, however, have been related to the low age of the cases in the study (≤ 40 years at diagnosis), and thus could be explained by the transient increase in risk following pregnancy that is also seen in the general population.[13] Hartge and colleagues[18] found that mothers of carriers of BRCA1 and BRCA2 mutations did not show the expected risk reduction associated with lower age at first birth and with an increasing number of births. In the recent study of Narod and colleagues[39] there was an increase in breast cancer risk in BRCA1 mutation carriers associated with use of oral contraceptives, especially at young ages. No association was present between breast cancer risk and parity in this large group of BRCA1 and BRCA2 mutation carriers.

The present study has the advantage of using prospective information on risk factors from a population-based cohort for BRCA2-positive cases, for BRCA2-negative cases and for unaffected controls. The study group was not restricted to young cases; the median age at diagnosis was 48.4 years (range 30-77 years) and the interaction between mutation status and number of pregnancies persisted after excluding cases diagnosed younger than the age of 40 years. We believe that matching on birth year and age when responding reduced confounding and random variation due to changes with time in reproductive and breast feeding habits.[30] A possible bias due to inclusion of 13 BRCA2-positive cases who were recruited because of family history was ruled out, since the exclusion of this subgroup did not affect the observed interaction between the mutation status and the number of births. The present study included only carriers of one specific BRCA2 founder mutation. However, it is probable that inferences can be drawn for carriers of other types of detrimental BRCA2 mutations since this mutation is a 5 base pair deletion in exon 9 leading to an early truncation of the BRCA2 protein. On the contrary, this study provides no information regarding carriers of BRCA1 mutations. The case groups were well defined but small, and thus there was relatively low power to detect the low relative risks associated with the effects of the reproductive variables according to earlier studies using the CDC cohort [9,10,12,30].

The lack of a significant positive association between breast cancer and age at first birth in the BRCA2-negative cases was rather unexpected since such a relationship has been confirmed in other studies based on the CDC cohort. However, the relationship has been found to be strongest in premenopausal cases.[10,12] The present lack of association could thus be explained by a low power to detect the association because there were only 245 cases in the BRCA2-negative group who were younger than age 55 years at diagnosis. Decreased breast cancer risk associated with breast feeding was mainly confined to young cases in a recent Icelandic study.[30] In accordance with the present results this might be related to the fact that 24% of breast cancer patients diagnosed younger than age 40 years in Iceland are carriers of the BRCA2 founder mutation [2].

Much is still unclear about the roles of the BRCA gene products in the biology of epithelial tissue, and explanations of the tissue specificity of the effects of mutations are lacking.[40] It is known, however, that the BRCA proteins are involved in basic cellular functions such as DNA repair, cell cycle control and transcription. More specifically, there are suggestions that the BRCA1 gene has a role in steroid hormone signalling.[6,7] Studies of the murine brca1 gene indicate that it is involved in the process of proliferation and differentiation in response to ovarian hormones.[41]

Support for a role of the BRCA1 gene relating to differentiation of breast tissue in humans comes from the work of Russo and colleagues. They have investigated the effects of pregnancies on the differentiation of epithelial cells in the mammary gland, both in animal models and in human breast tissue.[42,43,44,45] The results of Russo and colleagues underline the importance of undifferentiated cells in breast carcinogenesis, demonstrating their susceptibility to the effects of carcinogens contrary to differentiated structures that are less susceptible. Furthermore, Russo and colleagues have shown that, during the lifespan of a female, the breast tissue undergoes complicated developmental changes, and that parous women have generally much more complex lobular structures (lobules type 3) than nullipara (lobules type 1). In a recent study, Russo and colleagues' results indicated that women with a family history of breast cancer or with BRCA1 mutations have much less pronounced changes related to pregnancy, suggesting that the BRCA1 gene may have a functional role in the branching pattern of the breast during lobular development.[46]

Results of a recent study from our laboratory suggest that the product of not only the BRCA1 gene, but also the BRCA2 gene may have a role in the differentiation of breast epithelial cells.[8] The protein Stat5a belongs to a family of transcription factors that mediate the transcriptional response to a diverse group of cytokines and growth factors. Stat5a (mammary gland factor), which is essential for growth and terminal differentiation of breast epithelial cells and is strongly activated towards the end of pregnancy, was shown to form a complex with BRCA1 and BRCA2 proteins in breast epithelial cells upon stimulation with prolactin. Furthermore, the effects of Stat5a were modulated by both BRCA1 and BRCA2 proteins.

The hypothesis of the present study was that the association between breast cancer and age at menarche, pregnancies and breast feeding differed between women with and without the mutation. The hypothesis was supported for the number of pregnancies and the duration of breast feeding. A case-only design was used for estimating the interaction between reproductive variables and the BRCA2 mutation status. The validity of this approach has been shown to be dependent on the assumption of independence between the environmental and genetic factor.[47]

In this study it was not possible to verify this assumption. We could not check whether the number of children or the duration of breast feeding was associated with the mutation status because the prevalence of the mutation is very rare in the population[2] and only six carriers were expected among the controls. The interpretation of the results could therefore either be that hormones associated with pregnancies and with breast feeding affect breast cancer risk differently in mutation carriers and in noncarriers, or alternatively that mutation carriers are more likely to have an increased number of children (i.e. be more fertile) than other women and are more likely to present with a short duration of breast feeding due to an inherited reduced ability to breast feed. Even though increased fertility of the mutation carriers cannot be ruled out as an explanation for the observed association, the study by Russo and colleagues[46] supports a function of the BRCA1 gene in the process of differentiation as a response to ovarian hormones. The results cited earlier, indicating that the product of the BRCA2 gene might be important in the process of growth and terminal differentiation of breast epithelial cells, support that the same could be true for the BRCA2 gene.

With respect to potential problems with milk production of mutation carriers, there has been one report indicating that this could be true.[16] In the present study, information was not available relating to potential problems with breast feeding. The mutation carriers were just as likely to have ever breast fed as the other two groups, and a very short duration of breast feeding each child was as common among the mutation carriers as among the controls. The observed lower mean duration of lactation among the mutation carriers was due to lack of breast feeding for more than 6 months per child. The present results do not allow inferences to be drawn, with respect to potential problems with breast feeding.

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