Prolactin and Breast Cancer Risk in a Multiethnic Cohort

Institution: University of Southern California
Investigator(s): Brian Henderson, M.D. -
Award Cycle: 2003 (Cycle IX) Grant #: 9IB-0034 Award: $160,843
Award Type: IDEA
Research Priorities
Etiology and Prevention>Etiology: the role of environment and lifestyle



Initial Award Abstract (2003)
Prolactin (PRL) is important to breast development both during puberty and pregnancy, and it is the primary hormone responsible for milk production after pregnancy. Studies in animals and humans support the role of PRL as a possible hormonal risk factor for breast cancer. Elevated levels of prolactin have been positively associated with established breast cancer risk factors such as age at first full-term pregnancy, history of lactation, and number of live births. Studies also suggest that women with greater circulating PRL levels are at increased risk of breast cancer. Whether or not differences in prolactin levels are genetically determined has not yet been evaluated.

In this study we propose to investigate the association between genetic variations in PRL and PRL receptor (PRLR) and breast cancer risk among a multiethnic population from Hawaii and Los Angeles. We will also evaluate how common genetic in PRL and PRLR variations may relate to circulating plasma PRL levels.

We will employ high-throughput laboratory techniques and novel statistical methods to comprehensively evaluate genetic variation of the PRL and PRLR genes among Japanese, Caucasian, Hawaiian, African American, and Latina women from the Hawaii-Los Angeles Multiethnic Cohort Study (MEC). Common genetic variation in PRL and PRLR will then be evaluated in a large, breast cancer case-control study in the MEC (1356 incident breast cancer cases and 2701 controls). In addition, we will examine common variations in these genes in relation to circulating plasma PRL levels among unaffected women. Previously collected DNA and plasma PRL biospecimens at time of subject enrollment will be used for the analyses.

The proposed study will be the first investigation to evaluate genetic variations in PRL and PRLR in relation to breast cancer risk and circulating prolactin levels. Recent findings show that circulating prolactin levels confer greater than a two-fold increased risk of breast cancer among women in the highest quartile of hormone levels. This study will incorporate novel genetic research methods and assess differences in breast cancer risk and circulating hormone levels among a multiethnic population.


Final Report (2005)
Prolactin (PRL) is important to breast development both during puberty and pregnancy, and it is the primary hormone responsible for milk production after pregnancy. Animal studies and human in vitro studies support the role of PRL as a possible hormonal risk factor for breast cancer. The largest epidemiologic study of postmenopausal women reports a 34% increase in risk of breast cancer among women with the highest compared to lowest quartiles of circulating PRL levels.

We employed high-throughput laboratory techniques and novel statistical methods to comprehensively evaluate genetic variation in the prolactin (PRL) and prolactin receptor (PRLR) genes in relation to circulating PRL levels and breast cancer risk among African-American, Hawaiian, Japanese, Latina, and White women in the Multiethnic Cohort Study (MEC). We randomly selected a high density of single nucleotide polymorphisms (SNPs) every 3-5 kilobases (kb) to cover approximately 60 kb (kilobases) for PRL and 210 kb for PRLR that includes 20 kb upstream and 10 kb downstream of each gene.

Haplotype reconstruction was conducted using a multiethnic panel of 349 unaffected MEC participants. We also included genetic variation data from an ongoing resequencing project aimed at identifying rare missense and splice site variants of the coding regions of PRL and PRLR among 95 women with advanced breast cancer (19 in each ethnic group). Genotyping of “tagging” SNPs that best predicted the common haplotypes (htSNPs) were performed within a case-control study of 1,716 incident breast cancer cases and 2,505 controls of five different ethnic groups in the MEC. We collected circulating PRL levels on 500 female cohort controls (about 100 in each ethnic group) that were used in the haplotype-hormone level analysis.

For PRL, 62 SNPs (on average, 1 kb apart) and for PRLR, 105 SNPs (on average 2 kb apart) were observed at = 5% minor allele frequency in at least one ethnic group. In PRL, we defined 3 regions of linkage disequilibrium (LD), areas of low historical recombination, with block sizes of 14, 7, and kb, respectively, and for PRLR we identified 6 LD blocks sizes of 23, 21, 17, 22, 35, and 3 kb. A total of 21 (PRL) and 23 (PRLR) htSNPs were genotyped the breast cancer case-control study. The region between blocks 1 and 3 (20 kb) in PRL showed little evidence of LD; this region was called “block” 2 but was then also assessed using single SNP analyses. We genotyped a novel missense SNP in PRLR, discovered from the MEC sequencing project of advanced breast cancer cases (Ile100Leu in exon 5) in the case-control panel. No new missense SNPs were found in PRL from the MEC sequencing project to be evaluated with breast cancer risk.

We observed no association between PRL and PRLR haplotypes and breast cancer risk, or an association with any of the single SNPs in these genes and breast cancer risk. Overall, there was no strong evidence of an association between plasma PRL levels and haplotypes or with the missense SNP in PRLR. However, PRL levels were statistically significantly associated with SNP 35 (intron 1) in the region of low LD of PRL (p = 0.0005). Further studies among larger samples are needed to assess this relationship. The haplotype characterization of PRL and PRLR demonstrates the challenges in applying a haplotype block based approach in regions of low LD despite high SNP density; however, these findings provide a useful foundation for assessing common genetic variation in relation to other disease outcomes in the future.