Abstract P1-05-04: Progestin receptor content of breast cancer associated with expression of gene subsets for peptide/protein hormones and cognate receptors in LCM-procured cells that impact clinical outcomes
Authors: Daniels MW , Brock GN , James WL 
Published: February 2018

Assessing breast cancer prognosis and treatment selection was first enhanced by discovery that estrogen (ER) and progestin receptor (PR) proteins were clinically relevant biomarkers. Later reports suggested expression of certain protein hormones in breast cancer cells appear to be related to clinical behavior. We deciphered clinically relevant relationships between PR content in tissue biopsies and relative expression levels of genes directing synthesis of peptide/protein hormones and their cognate receptors in LCM-procured breast cancer cells. This global approach revealed unique relationships between both PR+ or PR- carcinomas and small subsets of genes for these peptide/protein hormones and cognate receptors as independent predictors of risk of recurrence.

Methods: Expression of genes for 61 peptide/protein hormones and 81 cognate receptor proteins were measured by microarray analyses of LCM-procured carcinoma cells from de-identified primary breast carcinoma biopsies. Using an IRB-approved biorepository and database, previously total RNA was extracted from carcinoma cells to determine expression levels of ˜22,000 genes. Univariable and multivariable Cox regressions with interaction of each hormone

eceptor gene, individually or paired, and use of LASSO were determined with relative gene expression values of each protein ligand and its cognate receptor. PR content and ligand binding affinity of each carcinoma were quantified by FDA approved assays.

Results: Using de-identified clinical outcomes that extended up to 12 years, univariable Cox regression analyses of 142 candidates revealed AVPR1A, AVPR2, CALCR, CRH, LHB, POMC, SCT, SST, SSTR1 and TMSB10 independently predicted PFS or OS. Violin plots identified candidate genes associated with PR content. Multivariable analyses of relative gene expression of 115 hormone-receptor pairs showed IAPP-CALCR, RLN2-RXFP1, GHRH-GHRHR, CGA-TSHR, EDN1-ENDRA and POMC-MC5R exhibited statistically significant interaction for predicting OS among 145 PR+ cancers. Four gene pairs (HCRT-HCRTR2, CRH-CRHR1, HCRT-HCRTR1 and CORT-SSTR4) were associated with OS among 101 PR- lesions. Using LASSO, PR+ lesions expressing either (CGA & SSTR2) or (CGA) predicted OS and PFS, respectively. Similarly, for PR- cancers, gene subsets (GRP, TMSB15, VIP2) or (AGT, GH1, GRP, TMSB15A) predicted OS and PFS, respectively. Three of four signatures were externally validated with SurvExpress.

Conclusion: Different gene expression profiles for protein hormones and cognate receptors were identified in PR+ or PR- carcinomas at time of diagnosis that predict PFS and OS regardless of treatment. Combining PR content with gene expression of LCM-procured cells is likely to provide insight into alternative treatments whereby standard of care performed poorly or to identify genes that correlate with cancer progression regardless of treatment modality. Collectively, results suggest that many primary breast cancers exhibit considerable endocrine autonomy for controlling disease progression, supporting investigation of protein products of gene candidates in isolated populations of breast carcinoma cells to develop novel biomarker assays.

Citation Format: Daniels MW, Brock GN, James WL. Progestin receptor content of breast cancer associated with expression of gene subsets for peptide/protein hormones and cognate receptors in LCM-procured cells that impact clinical outcomes [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-05-04.