Abstract P3-04-06: Expression of genes for peptide/protein hormones and their receptors in breast carcinomas as biomarkers predicting risk of recurrence
Authors: Wittliff JL , Daniels MW , Brock GN 
Published: May 2016

Background: Several reports have suggested expression of certain peptide/protein hormones in breast cancer cells appear to be related to clinical behavior. We have taken a global approach by evaluating relationships between genes for these hormones and their cognate receptor proteins as independent predictors of risk of recurrence.

Methods: Expression of genes for 55 peptide/protein hormones (the ligands) and 73 of their cognate receptor proteins were measured by microarray analyses of LCM-procured carcinoma cells from 247 breast carcinoma biopsies. Using an IRB-approved biorepository and comprehensive database, total RNA was extracted from carcinoma cells to determine expression levels of 22,000 genes. Univariate and multivariate Cox regressions with interaction were determined using expression values of each ligand and its cognate receptor with an interaction term.

Results: When pairs of hormone ligand and cognate receptor genes were evaluated by multivariate Cox regression with interaction, the following sets of genes were identified that predicted risk of breast cancer recurrence (INS/IGF2R, HAMP/SLC40A1, POMC/MC4R, GH1/GHR and VIP/VIPR2) and OS (CORT/SSTR5, VIP/VIPR2 and GHRH/GHRHR, based on unadjusted p-value for interaction term &lt; 0.05). Since expression in situ of both hormone and receptor are necessary to elicit endocrine action, a unique alternative approach using the minimum expression value between ligand and receptor for each patient was applied. These results revealed that the complex of HAMP/SLC40A1 showed significance in both the interaction and minimum models, and was further investigated by splitting the ligand and receptor into low (below 1st quartile) and high (above 1st quartile) expression groups. The group consisting of high expression for both ligand and receptor was contrasted with the other three groups (low expression for ligand, receptor, or both). The higher expression group exhibited a better DFS (hazard ratio (HR) = 0.56 95% CI 0.37-0.84, p=0.004) and OS (HR = 0.59 95% CI 0.37-0.93, p=0.022).

Conclusion: As a result of determining gene expression directly on pure populations of breast carcinoma cells procured by LCM, we have demonstrated the many lesions synthesize mRNA species for a wide variety of peptide and protein hormones as well as for their cognate receptor proteins. Using clinical follow-up that extended as much as 12 years, univariate and multivariate Cox regression analyses with and without interaction models revealed a number of noteworthy candidates of hormone-receptor complexes that predicted risk of breast cancer recurrence as well as overall survival. Collectively, our results suggests that many breast carcinomas exhibit considerable endocrine autonomy for controlling progression, which warrants investigation of the protein products of the gene candidates in isolated populations of breast carcinoma cells.

Citation Format: Wittliff JL, Daniels MW, Brock GN. Expression of genes for peptide/protein hormones and their receptors in breast carcinomas as biomarkers predicting risk of recurrence. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-04-06.