LaBaer Lab | Research

research: pathway mapping

Functional Genomics and Proteomics Studies to Uncover New Pathways Involved in Endocrine Resistance in Breast Cancer

Investigators: Laura Gonzalez, Ph.D. , Jin Park, Ph.D. Mike Gaskin, and Milen Vitanov

Collaborators: Hugo Arias-Pulido, Ph.D. (University of New Mexico Cancer Center), Juan Chavez, Ph.D. and Jim Bruce, Ph.D. (Washington University), Sutapa Barua, Ph.D. and Kaushal Rege, Ph.D. (Ira A. Fulton School of Engineering), Laimonas Kelbauskas, Ph.D., Shashanka Ashili, Ph.D. and Robert Ros, Ph.D. (ASU), Donald Chow, Ph.D. and Holly Yin, Ph.D. (TGen), Ann Mccullough, Ph.D. (Mayo Clinic), and PSOC centers from ASU (Paul Davies, Ph.D.) and USC (Shannon Mumenthaler, Ph.D. and Parag Mallick, Ph.D.)

We are interested in identify and characterize genes that regulate critical events involved in the progression of breast cancer and understanding the development of resistance to anti-estrogens, such as tamoxifen and fulvestrant. We have produced several matching drug sensitive and resistant breast cancer cultured cell lines that we can use to study the factors that lead to drug resistance. As a proof of concept, we focus on tamoxifen sensitive and resistant cells which provided a useful resource to study which genes are inappropriately regulated in the resistant state. This led to a signature that can predict overall patient survival in tamoxifen treated patients (Figure 1). We continue characterizing these sub-clones by their physical (PSOC), genomic (NextGen sequencing) and proteomic (USC) properties to better understand tamoxifen resistance.

We also used our clone collection of more than 500 human kinases in the development and execution of high throughput unbiased screens, as well as focused analyses of specific candidate genes, to identify those that made the tamoxifen sensitive sub-clones become resistant. Detailed investigation has now shown that one of these kinases, HSPB8, both confers resistance on sensitive cells when ectopically expressed by preventing autophagy (a process by which cells digest their own proteins) and kills resistant cells when knocked down by inducing autophagy (PNAS, 2011 108: 2058-2063).

HSPB8 is an atypical protein kinase with particularly elevated expression in breast cancers. Notably, higher expression levels of HSPB8 predicted an earlier relapse for breast cancer patients treated with tamoxifen in at least one cohort. To validate this result, we are currently analyzing the expression levels of HSPB8 in an independent set of breast cancer tissue samples (from the University of New Mexico Cancer Center and the Mayo Clinic). In parallel, we have continued with the characterization of the functional role of HSPB8 in autophagy and tamoxifen resistance by looking for proteins that it interacts with (Washington University). This will give us clues as how HSPB8 makes breast cancer cells resistant to tamoxifen.

Our results are leading to important new findings relating to genes that are involved in resistance to hormonal treatment in breast cancer. We will continue to use this approach with the hope to define gene pathways that are responsible for drug resistance; by doing this we can derive combined treatments that will more effectively treat resistant cancers (in collaboration with TGEN and the Ira A. Fulton School of Engineering).