Mean circulating levels of CSF1 were similar for cases (584.7 pg/ml, range 163.1–2170.5 pg/ml) and controls (583.7 pg/ml, range 169.7–2078.7 pg/ml). Among controls, circulating CSF1 was positively associated with BMI and weight gain since age 18 and inversely associated with alcohol consumption (). Women with the highest levels of circulating CSF1 were more likely to be postmenopausal, have a family history of breast cancer, and be parous than women with lower levels.
Age and age-adjusted characteristics among controls (N=734) according to CSF1 levels, Nurses' Health Study (1992–1998).
Overall, circulating CSF1 levels and risk of breast cancer (Ptrend =0.37; ) were not associated. However, the association varied by menopausal status (Pheterogeneity =0.009). Women with CSF1 levels in the highest (vs lowest) quartile had an 85% reduced risk of premenopausal breast cancer (RR=0.15, 95%CI 0.03–0.85, Ptrend =0.02) and a contrasting nonsignificant 33% increased risk of postmenopausal breast cancer (RR=1.33, 95%CI 0.96–1.86; Ptrend =0.11). The association between CSF1 and postmenopausal breast cancer appeared stronger when limited to invasive cancers (RR=1.45, 95%CI 1.02–2.07; Ptrend =0.06; ). CSF1 was associated with ER+/PR+ breast cancers (RR=1.72, 95%CI 1.11–2.66; ), but not ER−/PR− tumors (RR=0.70, 95%CI 0.34–1.44; Pheterogeneity=0.03; ).
Relative risk (RR) and 95% confidence interval of breast cancer associated with quartiles of circulating CSF1 in the Nurses' Health Study (1992–1998).
Relative risk (RR) and 95% confidence interval of postmenopausal breast cancer associated with quartiles of circulating CSF1 in the Nurses' Health Study (1992–1998) according to tumor characteristics.
Because we observed a strong positive association between circulating CSF1 with both weight gain since age 18 and current BMI (), and adiposity is a risk factor for breast cancer we also ran multivariate models adjusted for both weight gain since age 18 and current BMI (continuous). The results were essentially unchanged from those presented in and .
To understand the divergence of associations by menopausal status, we conducted stratified analyses among postmenopausal women with higher estrogen environments. However, the CSF1-breast cancer association was not modified by postmenopausal hormone use (Pheterogeneity=0.68) or BMI (Pheterogeneity=0.29).
To our knowledge, this is the first prospective study to examine circulating levels of CSF1 and subsequent risk of breast cancer. CSF1 was inversely related to premenopausal and positively associated with postmenopausal breast cancer. Although a priori we would not have predicted differential effects for CSF1 by menopausal status, the association of other exposures (e.g., BMI, circulating IGF1 levels) with breast cancer depends on menopausal status. The mechanism by which CSF1 may differentially influence premenopausal and postmenopausal breast cancer risk is unclear. Additional studies in premenopausal women are necessary to confirm these results.
One study suggests that CSF1 can influence breast cell proliferation either positively or negatively depending on the estrogen environment (14
). In ER+ cell lines, estradiol induced a three- to fivefold increase in growth, while CSF1 alone did not (14
). However, in combination, CSF1 inhibited the proliferative effects of estradiol by inducing G1 arrest. In contrast, earlier work in ER− cell lines showed that CSF1 induced proliferation (15
). These data suggest that in a high-estrogen environment CSF1 inhibits proliferative effects of mitogens such as estradiol.
Accumulating evidence supports a role for CSF1 in breast carcinogenesis. Activation of CSF1R causes uncontrolled growth (9
), increases the invasive potential of epithelial cells (17
), and promotes angiogenesis (18
). In animal models, blockade of CSF1 through anti-sense oligonucleotides or neutralizing anti-CSF1 antibodies suppressed tumor growth and prolonged long-term survival (19
). Thus, CSF1R may be a target for breast cancer chemoprevention.
This initial prospective study of circulating CSF1 levels suggests that CSF1 is a biomarker of subsequent postmenopausal breast cancer risk. Additional studies will be necessary to replicate these findings. This study was limited by the number of premenopausal breast cancer cases; it remains to be seen whether CSF1 has disparate effects in premenopausal and postmenopausal women.