Background: There is growing evidence that ADAM (a disintegrin and metalloproteinase) family proteins are involved in multiple types of cancer, including breast cancer. More than 50 members of the ADAM family have been identified thus far. Previous studies have focused on one or two ADAMs but comparative research among the members of the family is lacking. This study was undertaken to identify the most important ADAMs associated with breast cancer.

Methods: We analyzed mRNA expression of ADAMs in tumor bed stroma and paired normal adjacent stroma from 31 breast cancer patients. The original raw data was adapted from a breast dataset (Finak et al, 2008). We next analyzed RNA expression of 35 ADAMs in different subtypes of breast cancers [dataset from Affymetrix U133A arrays using methods available in the R statistical software package (http://cran.r-project.org)]. We further evaluated protein expression of ADAMs and related signaling molecules in 187 breast cancers, including 110 untreated primary tumors and 77 residual tumors after neoadjuvant chemotherapy, and 167 matched ‘normal’ mammary tissues using reverse phase protein arrays (RPPA). The association between ADAMs expression and survival was analyzed using Kaplan–Meier analysis.

Results: The microarray analysis of tumor bed stroma revealed significantly elevated mRNA levels of 12 ADAMs, including ADAM8, ADAM 12, ADAM 19, ADAM 21, ADAM 17, ADAM 10, ADAM 28, ADAM 7, ADAM 33, ADAM 22, ADAM 6 and ADAMTS20, compared to their normal adjacent stroma. We evaluated the expression of 35 ADAMs in total 369 breast cancers, including 201 hormone receptor positive (HR+), 60 HER2 amplified (HER2+) and 108 triple negative (TN) patients using RNA array and demonstrated that 24 of 35 ADAMs were significantly upregulated in TNBC compared to that in HR+ and HER2+ subtypes. We further analyzed protein expression of ADAMs in 189 breast cancers and 172 matched “normal” breast tissues with RPPA. Compared to “normal” breast tissues, ADAM17, ADAM10, ADAM15, ADAM8 and ADAM9 were significantly increased in tumors (P < 0.0001, respectively), while ADAM20, ADAM23, ADAM29, and ADAM30 exhibited lower level. Kaplan–Meier analysis showed that 13-year overall survival rate in high expression of ADAM 17, ADAM 15 or ADAM10 group was significantly decreased compared to that in the low expression group (40% vs. 12%, P = 0.0026; 50% vs. 11%, P = 0.0104; 53% vs. 9%, P < 0.0001, respectively), suggesting that upregulation of ADAM17, ADAM15, or ADAM10 was significantly associated with poor outcome. ADAM17, ADAM9 or ADAM10 expression was tightly associated with elevation of anti-apoptotic molecule Bcl-X, cyclins (E1, E2, B1), PTPN12, and phosphorylation of 4-EBP1.

Conclusion: Several ADAM proteins have elevated expression in breast cancer and are associated with decreased patient survival. ADAMs may, therefore, serve as potential biomarkers for predicting outcomes and oncotargets in breast cancer.

Citation Format: Shuying Liu, Michael Z. Gilcrease, Huiqin Chen, Wenbin Liu, Fan Zhang, Kim-Anh Do, Gordon B. Mills, William F. Symmans, Naoto T. Ueno, Ana M. Gonzales-Angulo, Gabriel N. Hortobagyi, Debasish Tripathy. ADAMs: potential biomarkers and oncotargets in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4736. doi:10.1158/1538-7445.AM2017-4736