Abstract P1-01-12: Expression of autophagy related genes impacts clinical outcomes of human breast carcinoma and is associated with estrogen and progestin receptor status
Authors: Wittliff JL , Hameed ZR , Daniels MW , Cheng A 
Published: February 2018

The dual role of autophagy in breast cancer initiation, progression and responsiveness to various therapies is the focus of extensive studies. Our goal is to assess the relationship of expression of certain autophagy related genes in primary breast carcinomas to predict risk of recurrence. Our hypothesis includes the caveat that unique gene expression subsets will be deciphered by utilizing Laser Capture Microdissected breast carcinoma cells from tissue biopsies containing many cell types.

Methods: Comprehensive analyses of de-identified biomarker results, characteristics of 247 breast carcinoma specimens and clinical outcomes were performed by univariable Cox regressions, Kaplan Meier plots and LASSO with R software version 3.2.5. Microarray analyses were performed on RNA isolated from LCM-procured carcinoma cells to identify gene signatures associated with breast cancer behavior.

Results: Expression levels of 22 autophagy related genes analyzed by univariable Cox regression revealed that RB1CC1, KEAP1, ATG7, RUBCN, NOD2, HMOX1, BECN1, PIK3R4 were significant for predicting Progression Free Survival (PFS) at the discovery level of the adjusted p-value &lt; 0.3. Of these, RB1CC1, KEAP1, & ATG7 were significant for Overall Survival (OS) without regard to ER/PR status. Using Kaplan Meier analyses, expression levels of each of 10 candidate genes predicted PFS of which expression of 6 of these genes also predicted OS using a median split cutoff without regard to ER/PR status. Applying LASSO computations without regard to ER/PR status of the primary breast cancer, a clinically relevant gene expression profile consisting of ATG7, BCL2, HMOX1, KEAP1, NOD2, PTEN, RB1CC1, and ULK4 predicted PFS. Collectively, expression of these 8 genes with TP53 and RUBCN predicted OS without regard to ER/PR status. Violin plots of relative gene expression of each of the 22 candidate genes known to be associated with autophagy pathways revealed that ATG7, ATG12, BCL2 and BECN1 were elevated in ER+ lesions while BCL2 and BECN1 were also elevated in PR+ breast carcinomas. Expression levels of 16 of the 22 autophagy related genes examined by univariable Cox regression were related to either ER or PR status of the primary lesion and predicted either PFS or OS. Refinement of clinically relevant gene subsets was accomplished by LASSO calculations in which either the ER or PR protein status of the primary breast carcinoma was considered. Of the genes in the molecular signatures derived, expression levels in breast carcinomas separated by either ER or PR status of the lesion were tested by Kaplan Meier analyses to assess relationships to PFS and OS.

Conclusions: Using gene expression results derived from microarray analyses of LCM-procured breast carcinoma cells of primary lesions, subsets of autophagy related genes were identified that predict a patient's risk of recurrence and overall survival. Expression of a number of candidate genes appears to be related to either/both the ER or PR protein status of the primary lesion. Collectively, results suggest that expression of certain autophagy related genes may serve as biomarkers for assessing prognosis of breast carcinoma thus impacting clinical management of breast cancer.

Citation Format: Wittliff JL, Hameed ZR, Daniels MW, Cheng A. Expression of autophagy related genes impacts clinical outcomes of human breast carcinoma and is associated with estrogen and progestin receptor status [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 P1-01-12.