Faculty Bibliography

BACKGROUND:Full-term pregnancy (FTP) at an early age confers long-term protection against breast cancer. Previously, we reported that a FTP imprints a specific gene expression profile in the breast of postmenopausal women. Herein, we evaluated gene expression changes induced by parity in the breast of premenopausal women. METHODS:Gene expression profiling of normal breast tissue from 30 nulliparous (NP) and 79 parous (P) premenopausal volunteers was performed using Affymetrix microarrays. In addition to a discovery/validation analysis, we conducted an analysis of gene expression differences in P vs. NP women as a function of time since last FTP. Finally, a laser capture microdissection substudy was performed to compare the gene expression profile in the whole breast biopsy with that in the epithelial and stromal tissues. RESULTS:Discovery/validation analysis identified 43 differentially expressed genes in P vs. NP breast. Analysis of expression as a function of time since FTP revealed 286 differentially expressed genes (238 up- and 48 downregulated) comparing all P vs. all NP, and/or P women whose last FTP was less than 5 years before biopsy vs. all NP women. The upregulated genes showed three expression patterns: (1) transient: genes upregulated after FTP but whose expression levels returned to NP levels. These genes were mainly related to immune response, specifically activation of T cells. (2) Long-term changing: genes upregulated following FTP, whose expression levels decreased with increasing time since FTP but did not return to NP levels. These were related to immune response and development. (3) Long-term constant: genes that remained upregulated in parous compared to nulliparous breast, independently of time since FTP. These were mainly involved in development/cell differentiation processes, and also chromatin remodeling. Lastly, we found that the gene expression in whole tissue was a weighted average of the expression in epithelial and stromal tissues. CONCLUSIONS:Genes transiently activated by FTP may have a role in protecting the mammary gland against neoplastically transformed cells through activation of T cells. Furthermore, chromatin remodeling and cell differentiation, represented by the genes that are maintained upregulated long after the FTP, may be responsible for the lasting preventive effect against breast cancer.

BACKGROUND: Pregnancy and parity are associated with subsequent breast cancer risk. Experimental and epidemiologic data suggest a role for pregnancy sex steroid hormones. METHODS: We conducted a nested case-control study in the Northern Sweden Maternity Cohort (1975-2007). Eligible women had provided a blood sample in the first 20 weeks of gestation during a primiparous pregnancy leading to a term delivery. The current study includes 223 cases and 417 matched controls (matching factors: age at and date of blood collection). Estrogen receptor (ER) and progesterone receptor (PR) status was available for all cases; androgen receptor (AR) data were available for 41% of cases (n = 92). Sex steroids were quantified by high-performance liquid chromatography tandem mass spectrometry. Odds ratios (ORs) and 95% confidence intervals were estimated using conditional logistic regression. RESULTS: Higher concentrations of circulating progesterone in early pregnancy were inversely associated with ER+/PR+ breast cancer risk (ORlog2: 0.64 (0.41-1.00)). Higher testosterone was positively associated with ER+/PR+ disease risk (ORlog2: 1.57 (1.13-2.18)). Early pregnancy estrogens were not associated with risk, except for relatively high estradiol in the context of low progesterone (split at median, relative to low concentrations of both; OR: 1.87 (1.11-3.16)). None of the investigated hormones were associated with ER-/PR- disease, or with AR+ or AR+/ER+/PR+ disease. CONCLUSIONS: Consistent with experimental models, high progesterone in early pregnancy was associated with lower risk of ER+/PR+ breast cancer in the mother. High circulating testosterone in early pregnancy, which likely reflects nonpregnant premenopausal exposure, was associated with higher risk of ER+/PR+ disease.

Human chorionic gonadotropin (hCG) is necessary for the maintenance of early pregnancy and promotes normal breast cell differentiation. Administered hCG reduces risk of carcinogen-induced breast cancer in animal models, and higher circulating hCG concentrations were associated with significantly lower long-term risk of breast cancer in a prior nested case-control study. In this study, we investigated early pregnancy hCG concentrations and subsequent breast cancer risk. We conducted a nested case-control study with 1,191 cases and 2,257 controls (matched on age and date at blood collection) in the Finnish Maternity Cohort (FMC), a cohort with serum samples from 98% of pregnancies registered in Finland since 1983. This study included women with a serum sample collected early (<140 days gestation) in their first pregnancy resulting in a live, term birth. Breast cancer cases were identified via the Finnish Cancer Registry. Age at breast cancer diagnosis ranged from 22-58 years (mean: 41 years). hCG was measured using a solidphase competitive chemiluminescence assay. Odds ratios (ORs) were calculated using conditional logistic regression. We observed no association between hCG and breast cancer risk, overall (Quartile 4 vs. 1, OR: 1.14 95% confidence interval [0.94-1.39], by estrogen and progesterone receptor status, or by ages at first term birth or diagnosis. Associations did not differ by time between pregnancy and diagnosis (e.g., <5 years, ORQ4 vs. Q1: 1.10 [0.64-1.89]; {greater than or equal to}15 years, ORQ4 vs. Q1: 1.36 [0.86-2.13]; pheterogeneity=0.62). This large prospective study does not support an inverse relationship between early pregnancy serum hCG concentrations and breast cancer risk.

Pregnancy, parity and circulating steroid hormone levels are associated with risk of breast cancer, but little is known about hormone concentrations during pregnancy and subsequent breast cancer risk. We evaluated early pregnancy (<140 days gestation) serum estradiol, estrone, progesterone, and testosterone and breast cancer risk in a nested case-control study in the Finnish Maternity Cohort. The cohort includes 98% of pregnancies registered in Finland since 1983. Individuals with samples collected in the first pregnancy leading to a live birth were eligible. Breast cancer cases (n=1,199) were identified through linkage with the Finnish Cancer Registry; 2,281 matched controls were selected using incidence density sampling. Odds ratios were calculated using conditional logistic regression. Hormone concentrations were not associated with breast cancer overall. Estradiol was positively associated with risk of breast cancer diagnosed age <40 (4th vs. 1st quartile OR 1.60 (1.07-2.39); ptrend=0.01), and inversely associated with breast cancer diagnosed at age >/=40 (4th vs. 1st quartile OR 0.71 (0.51-1.00); ptrend=0.02). Elevated concentrations of the steroid hormones were associated with increased risk of estrogen receptor (ER) and progesterone receptor (PR) negative tumors in women age <40 at diagnosis. We observed no association between steroid hormones and ER+/PR+ disease. These data suggest a positive association between high concentrations of early pregnancy steroid hormones and risk of ER-/PR- breast cancer in women diagnosed age <40, and an inverse association for overall breast cancer diagnosed age >/=40. Further research on pregnancy hormones and risk of steroid receptor negative cancers is needed to further characterize this association.

Background: It has been hypothesized that predominance of the 2-hydroxylation estrogen metabolism pathway over the 16alpha-hydroxylation pathway may be inversely associated with breast cancer risk. Methods: We examined the associations of invasive breast cancer risk with circulating 2-OHE1, 16alpha-OHE1, and the 2-OHE1:16alpha-OHE1 ratio in a case-control study of postmenopausal women nested within two prospective cohorts: the New York University Women's Health Study (NYUWHS) and the Northern Sweden Mammary Screening Cohort (NSMSC), with adjustment for circulating levels of estrone, and additional analyses by tumor estrogen receptor (ER) status. Levels of 2-OHE1 and 16alpha-OHE1 were measured using ESTRAMET 2/16 assay in stored serum or plasma samples from 499 incident breast cancer cases and 499 controls, who were matched on cohort, age, and date of blood donation. Results: Overall, no significant associations were observed between breast cancer risk and circulating levels of 2-OHE1, 16alpha-OHE1, or their ratio in either cohort and in combined analyses. For 2-OHE1, there was evidence of heterogeneity by ER status in models adjusting for estrone (p