Abstract 3676: The use of r-hCG changes the transcriptome profile of nulliparous women carrying BRCA1 mutation

Abstract

Abstract Nulliparity and inheritance of BRCA1 or BRCA2 mutations are conditions associated with a greater risk of developing breast cancer. The knowledge that early parity reduces a woman's lifetime cancer risk and the demonstration in preclinical studies that the protective effect of pregnancy is mediated by the differentiation of the breast, which is manifested as permanent changes in the genomic/transcriptomic profile of this organ, led us to hypothesize that the transcriptomic profile of breast tissue of nulliparous BRCA1 mutation carriers would revert from high risk to lower risk after a short treatment with recombinant human chorionic gonadotropin (r-hCG). For this purpose we designed a pilot study for determining whether treatment of sexually mature, from 20 to 40 years of age, nulliparous women carriers of BRCA1 mutations with the r-hCG changes their breast epithelium's genomic profile to one similar to that identified in cancer-free postmenopausal women with a history of full term pregnancy. After signing an informed consent form, eligible candidates received 250 micrograms r-hCG applied as a subcutaneous injection 3 times a week for 12 weeks. Before initiation of treatment (T0), at the end (T12), and 24 weeks post-treatment (T24) a breast core needle biopsy (CNB) was performed by the study surgeon. In this proof of concept, tissues obtained from two volunteers were divided for histopathological and RNA analyses. Total RNA was extracted, prepared for hybridization using Two-Cycle Target Labeling and Control Reagents kits from Affymetrix, and hybridization to Affymetrix Human Genome U133 Plus 2.0 chips. The chips were analyzed using GeneSpring GX v11.0 software (Agilent Technologies). Comparison of gene expression between T0 and T24 revealed 425 probes (254 up- and 171 down-regulated), representing 349 unique differentially expressed genes (p-value< 0.01). Gene Ontology (GO) analysis revealed that enriched biological processes (p<0.1) were related mainly to regulation of gene expression and transcription, such as chromatin-mediated maintenance of transcription (GO:0048096); regulation of DNA-dependent transcription (GO:0006355); positive regulation of epigenetic gene expression (GO:0045815), and RNA metabolic process (GO:0051252). Regulation of genes related to splicing factors (SF3A1, SFRS12IP1); RNA binding motifs proteins (RBM12, RBM12B, RBM16, RBM22), and methyltransferase like (METTL9, METTL14) was also observed. The changes in the breast's transcriptomic pattern induced by the r-hCG treatment were similar to those that have been detected in cancer-free postmenopausal parous women. These observations led us to conclude that this short term hormonal treatment activates biological processes that could confer a degree of protection from developing breast cancer similar to that induced by pregnancy. (Study supported by NCI grant R21 CA124522). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3676. doi:10.1158/1538-7445.AM2011-3676