Abstract P2-05-25: TIMP-4 expression correlates with disease progression among HER2-positive breast cancers
Authors: Isaac KM , Zemba-Palko V , Sabol JL , Blair L , Behbod F , Wallon UM 
Published: May 2016

Breast cancer with HER2 gene amplification accounts for 20-25% of invasive breast cancer. HER2 activates the PI3K/Akt and MAPK pathways promoting survival and cell proliferation resulting in aggressive biological behavior and poorer prognosis for the patient. Although trastuzumab (Herceptin®), a recombinant humanized antibody, offers effective treatment of HER2-positive cancers, a proportion of patients will not respond to trastuzumab-based regimens and those who do respond can lose clinical benefit during the late stages of their treatment.

In this IRB-approved study we have assessed HER2 and LuminalB subtypes of invasive breast cancer from an archival collection together with specimens collected in an on-going prospective study for the expression of tissue inhibitor of metalloproteinase-4 (TIMP-4), an inducer of the PI3K/Akt pathway and its possible correlation to trastuzumab resistance. Circulating TIMP-4 in the stroma binds to CD63 on the tumor epithelial cells and initiates a signaling cascade through interaction with β1-integrin.

We have previously demonstrated that elevated levels of TIMP-4 confers poor survival prognosis for triple-negative breast cancers. Genomics data found at TCGA, cBioPortal for Cancer Genomics1 have showed that TIMP-4 is amplified in 24% of breast cancer patients.

Therefore, we propose that the reported ˜20% of HER2-positive patients that will not respond to trastuzumab could in fact be TIMP-4 positive and have active PI3K/Akt signaling. In this on-going study, we have to date examined twenty-nine patients with HER2 gene amplification. Among these, eight had elevated levels of TIMP-4 as determined by immunohistochemistry, and seven had progression of their disease within one year of starting systemic therapy (all with metastasis to brain) while one had local recurrence 5 years after starting therapy. Two of these patients had stage IA disease, one had IIA, three had IIB and two were diagnosed with stage IIIC disease. These results suggest that TIMP-4 amplification could be, at least in part, responsible for the trastuzumab resistance due to TIMP4's ability to promote survival and cell proliferation by a continuous activation of the PI3K/Akt pathway.

In an attempt to test if a monoclonal antibody specific for human TIMP-4 could be used to prevent or alleviate the trastuzumab resistance, we are using human breast cancer cell-lines with amplified HER2, with and without CD63 expression as well as a CD63 knock-out line. From these experiments we hope to learn if treating for TIMP-4 could be an approach for future clinical intervention for the patients that have HER2 gene amplification and elevated levels of TIMP-4.

1 Gao et al. Sci Signal. 2013 and Cermi et al . Cancer Discov. 2012.

Citation Format: Isaac KM, Zemba-Palko V, Sabol JL, Blair L, Behbod F, Wallon UM. TIMP-4 expression correlates with disease progression among HER2-positive breast cancers. [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 P2-05-25.