Abstract P3-05-11: Clinical outcomes of estrogen-receptor negative breast carcinoma are associated with protein hormone-cognate receptor gene expression
Authors: Daniels MW , Wittliff JL , Brock GN 
Published: March 2017

Background: Since certain protein hormones appear to be associated with progression of breast cancer cells in vitro, we employed a global approach by evaluating relationships between genes for these hormones and their cognate receptors in human breast cancer biopsies as independent predictors of risk of recurrence. Our goal is to derive clinically relevant molecular signatures correlating various ER/PR subtypes.

Methods: Microarray analyses of LCM-procured carcinoma cells from 247 de-identified biopsies determined expression of genes for 61 protein hormones (the ligands) and 81 cognate receptors. Total RNA was extracted, purified and amplified from cells to determine expression of 22,000 genes. Univariable and multivariable Cox regressions were determined using expression levels of each hormone/receptor gene. Kaplan-Meier plots were constructed with an adjusted p-value &lt;0.30 (discovery cutoff) for each gene candidates with/without ER status of the lesion. Cox regression analyses with/without interaction models deciphered candidates of hormone-receptor complexes that predicted risk of recurrence as well as overall survival using clinical follow-up that extended as much as 12 years. LASSO was used to derive gene subsets to predict overall survival (OS) and progression free survival (PFS) within ER/PR subtypes.

Results: Expression levels of 7 genes for protein hormones and 10 receptor genes were significant for OS at an adjusted p-value of &lt;0.30 while expression of 15 hormone and 19 receptor genes were significant for PFS without regard to ER/PR subtypes. When expression levels were considered with ER status only, 3 genes for ER+ lesions and 6 genes for ER- lesions were identified that predicted OS/PFS. Categorization of cancers according to combined ER and PR status revealed one gene for ER+/PR+, 3 genes for ER+/PR- and 2 genes for ER-/PR- associated with PFS/OS. After stratifying gene expression into above/below median for the linear predictor, Kaplan-Meier plots revealed patient groups with each signature for ER+/PR+, ER-/PR- and ER- lesions that exhibited significantly different survival. Molecular signatures comprising 16 genes for ER+/PR+ carcinomas, 10 genes for ER-/PR- lesions and 6 genes for ER- carcinomas predicted clinical outcomes with C-indices of 0.79, 0.76 and 0.71, respectively.

Conclusion: We revealed many breast carcinomas synthesize mRNA species for various protein hormones and their cognate receptors by determining gene expression directly on pure populations of these cells procured by LCM. We report a novel ten-gene ER-/PR- signature containing four genes in common with that of a six-gene ER- only signature that predicts breast cancer recurrence. Collectively, results of mRNA expression suggest that often breast carcinomas exhibit substantial elements of endocrine autonomy for regulating progression, warranting investigation of protein products of gene candidates in isolated populations of breast carcinoma cells.

Citation Format: Daniels MW, Wittliff JL, Brock GN. Clinical outcomes of estrogen-receptor negative breast carcinoma are associated with protein hormone-cognate receptor gene expression [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-05-11.