Abstract 440: The TRiC chaperonin in breast cancer cell growth, survival and response to taxane therapy
Authors: Guest Stephen , Irish Jon , Kratche Zachary , Garrett-Mayer Elizabeth , Wilson Robert , Ethier Stephen 
Published: May 2015

Large-scale efforts such as The Cancer Genome Atlas (TCGA) have identified the landscape of genetic, epigenetic and proteomic alterations in breast cancer through analysis of ∼1000 primary breast tumors. Importantly, all of the samples analyzed by TCGA also come with long-term clinical follow-up data that allows for examination of how identified alterations affect patient outcomes. Although powerful, the sheer number of alterations identified by TCGA and similar efforts makes it difficult to separate alterations that drive cancer from those that are merely passengers. We have been combining data from TCGA with data from genome-wide, RNAi-based, functional genetic screens that we have been performing on a panel of breast cancer cell lines that were developed in our lab. This combination of functional genetic data with data from the TCGA has resulted in the identification of genes that are responsible for driving breast cancer cell growth and survival that also affect patient outcomes. Using this approach, we have identified the TRiC chaperonin protein complex as playing a critical role in driving breast cancer and affecting patient outcomes. In the SUM-52 breast cancer cell line, a member of the TRiC complex known as TCP-1 was a hit in the genome wide, RNAi-based screen and examination of TCP1 in the TCGA database revealed that it is altered in ∼9% (85 of 929 cases) of breast cancers and patients with TCP1 alterations have significantly reduced long-term survival (pval&lt;.0000001). Expression of this gene was found to be regulated by a known driver oncogene in this cell line, FGFR2, and we have identified the PI3K signaling pathway as the mediator of this regulation. Examination of additional cell lines in our panel showed that TCP-1 expression is regulated by driver oncogene activity in multiple breast cancer cell lines e.g. HER2 in SUM-225 cells. Knocking down TCP-1 resulted in a dramatic decrease in the colony forming ability of the SUM-52 cell line while a much weaker effect on colony forming is observed in MCF10A cells, suggesting differential dependency on TRiC activity between transformed and non-transformed cells. Interestingly, a second member of TRiC was also a hit in the genome-wide RNAi screen in SUM-52 cells. Although not regulated by FGFR2, this gene is amplified and overexpressed in this cell line, and examination of TCGA data showed that ∼12% (113/929) of all breast cancers overexpress CCT2 and, these patients display a survival disadvantage (pval&lt;.005) the severity of which correlates with increased CCT2 expression levels. Similar to TCP-1, knocking down CCT2 significantly reduces the colony forming ability of the SUM-52 cell line. The identification of two genes that function as part of the same complex, both up-regulated by different mechanisms in breast cancer cells and both determinants of long term survival, points to a significant role for these genes and the TRiC complex in breast cancer.

Citation Format: Stephen Guest, Jon Irish, Zachary Kratche, Elizabeth Garrett-Mayer, Robert Wilson, Stephen Ethier. The TRiC chaperonin in breast cancer cell growth, survival and response to taxane therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 440. doi:10.1158/1538-7445.AM2014-440