The present results suggest that higher parity is associated with an increased risk of ER−/PR− breast cancer, but that breastfeeding ameliorates this adverse effect. Analyses stratified by time last since birth indicated that the association is not accounted for by the transient increase in risk in the period immediately following a full-term pregnancy. Results for parity and lactation in relation to ER+/PR+ subtype were strikingly different. Higher parity was associated with a reduced risk of ER+/PR+ breast cancer, and breastfeeding did not alter this association.
An inverse association of parity with risk of ER+ breast cancer has been consistently found,(12
) whereas studies of ER− breast cancer indicate either no association(12
) or a positive association.(18
) Among studies that also considered HER2 status, one found higher parity to be strongly associated with increased risk of both ER−/ PR−/ HER2− (“triple negative”) cancer and ER−/PR−/HER2+ cancer,(22
) one found high parity to be associated with increased risk of triple negative breast cancer only, (18
) and two studies were null.(16
) In two case-case analyses that compared the triple negative breast cancer subtype with ER+/PR+ subtype, one found a strong positive association of parity with the triple negative subtype, (21
) and the other found a similar positive association of parity with ER−/PR−/HER2+ tumors.(20
) Results of studies of “intrinsic” breast cancer subtypes (19
) as characterized by immunohistochemistry of several additional molecular markers also support these associations. The basal-like subtype characterized by ER−, PR−, HER2−, HER1+ and/or CK5/6 occurs more frequently in African Americans than in other ethnic groups and carries a poorer prognosis.(3
) In a case-control study from Poland, high parity was associated with an increased risk of basal-like breast cancer and a reduced risk of luminal A breast cancer (ER+ and/or PR+, HER2−).(23
) In the Carolina Breast Cancer Study, high parity was also positively associated with basal-like breast cancer and inversely associated with luminal A cancer.(19
The limited data from previous studies regarding the association of both lactation and parity with incidence of the ER− subtype are generally consistent with our findings. In the Carolina Breast Cancer Study,(19
) breastfeeding was associated with a reduced risk of basal-like but not luminal A subtype. In addition, the increased risk associated with parity was present only among women who had never breast fed; among women who had breast fed, there was essentially no association of parity with risk of basal-like breast cancer. The two case-only studies described above both observed a reduced risk of triple negative breast cancer associated with lactation,(20
) and, in one, the positive association of parity with triple negative breast cancer was present only among women who had never breastfed.(20
Why might full-term pregnancy, in the absence of breastfeeding, lead to an increased risk of ER− breast cancer? Schedin et al. hypothesized that the adverse effect of pregnancy may relate to immune system / inflammatory processes that occur during post-partum involution.(30
) Involution involves processes of wound healing and immunosuppression, both of which are known to be pre-tumorigenic. During involution, there is an influx of immune cells, activation of fibroblasts, and extracellular matrix deposition which resembles a pre-tumorigenic wounding environment.(33
) Mouse studies have shown that numerous immune-related genes are upregulated during involution.(34
) Lactation may mitigate the increased risk from full-term pregnancy by increasing the time between pregnancy and involution, thus lessening the chances that these two events (increase in estrogen levels during pregnancy and postpartum wound healing) will act synergistically to promote progression of previously initiated cells. Further, lactation may prevent disordered involution, characterized by increased inflammation of the mammary tissue. In women who breastfeed, involution is more likely to occur over a period of weeks or months as physiologic weaning takes place; thus, mammary tissue returns to its prepregnant state in a more coordinated process of apoptosis and remodeling.(35
) Under these postulated mechanisms, lactation could have a protective effect on all subtypes of breast cancer. We did not, however, observe an association of lactation with risk of ER+/PR+ breast cancer; it is possible that the beneficial effects of lactation on involution may be less important for hormone-positive breast cancer where hormonal influences have a dominant role.
In our analyses of ER− breast cancer, the inverse association with lactation was strongest in the group of women who had a first degree family history of breast cancer. This finding is consistent with a recent report from the Nurses’ Health Study II,(36
) which showed that among young women with a family history of breast cancer, those who had breastfed or used lactation suppression medications had a reduced risk of breast cancer compared with women who neither breastfed nor used such medications. The authors hypothesized that both lactation and use of lactation suppression medications could reduce breast cancer risk by preventing disordered involution.
Differences in inflammatory profiles between women of African ancestry and other women may be relevant to our finding of an association of parity in the absence of lactation with risk of ER− breast cancer in African American women. Several markers of inflammation, including C-reactive protein, serum amyloid, and IL-6, are elevated in African Americans.(37
) A robust immune system has an evolutionary advantage for populations living in sub-Saharan Africa where there has been endemic infectious disease. Genetic profiles have developed over millennia to adapt to these conditions. While these characteristics are advantageous for women living in Africa, the very strong immune response may be disadvantageous in other situations and could lead to an increased risk of aggressive breast tumors following pregnancy without lactation, due to the inflammatory processes accompanying involution. There have been several examples of genetic traits that are beneficial in some environments but detrimental in others. Murine studies show that specific malaria-driven genetic changes, such as loss of the Duffy antigen receptor, result in higher serum chemokine levels and an increased inflammatory milieu, predisposing to the development of more aggressive prostate tumors.(42
) More recently, two APOL1
variants that are common in African chromosomes but absent from European chromosomes were shown to be strongly associated with kidney disease.(43
) The variants reside within haplotypes that harbor signatures of positive selection. The protein ApoL1 is a trypanolytic factor that confers resistance to the otherwise deadly infection from the trypanosoma brucei brucei
parasite. We hypothesize that interactions of immune profiles with pregnancy and lactation may lead to an increased risk of ER− and basal-like breast cancers; the association may be seen most clearly in African Americans, who typically have a more robust inflammatory response. As discussed above, similar mechanisms may be involved in the etiology of ER+ breast cancer as well but may have a minor role relative to the powerful impact of hormone levels on this subtype.
Late age at first birth and recent birth (within 10 years) were associated with increased risk of both ER+ and ER− breast cancer in the present study. Most previous studies have found later age at first birth to be positively associated with ER+ breast cancer only or with both ER+ and ER− breast cancer.(12
) In contrast, the Carolina Breast Cancer Study observed an association with basal-like but not luminal-A cancers.(19
) Most studies to date have not reported on time since last pregnancy by ER/PR status.
Strengths of the present study include the prospective data collection, high response rate, large sample size, and control for a large number of breast cancer risk factors. Notably, this is the first prospective study with sufficient numbers to assess reproductive factors in relation to ER−/PR− breast cancer among African American women. A limitation is that data on ER/PR status were unavailable for 40% of breast cancer cases because many cases were diagnosed before immunohistochemistry was routinely carried out on tumor tissue. However, cases with and without hormone receptor status data were closely similar with regard to reproductive factors and other breast cancer risk factors, mitigating concern about selection bias. We were unable to assess subtypes according to HER2 expression, but previous studies suggest that HER2 status does not modify associations with the ER− subtype. Our ability to assess associations by duration of breastfeeding was limited because most participants who had breastfed had done so for less than 12 months total.
In summary, the present findings suggest that higher parity is associated with an increased risk of ER−/PR− breast cancer in African American women. Since African American women have had more births on average than U.S. white women,(44
) this association may explain, in part, why incidence of ER−/PR− breast cancer is higher in African American than white women. Further, the results provide evidence of a protective effect of lactation on ER−/PR− cancer, at least among women who have a family history of breast cancer. Uptake of breastfeeding has been considerably lower in African American women than in other ethnic groups in spite of efforts to convince women of its numerous health benefits.(45
) Our results, taken together with recent results from studies of triple negative and basal-like breast cancer, suggest that breastfeeding can reduce risk of developing the aggressive, difficult-to-treat breast cancers that disproportionately affect African American women.