Abstract A30: PELP1 and AIB1 cooperate to promote breast cancer progression in ER+ breast cancer models

Luminal breast cancers account for ~75% of newly diagnosed cases and express estrogen receptor (ER) and a range of progesterone receptor (PR)-positive cells. Although adjuvant hormone therapies that target ER actions (e.g., tamoxifen or aromatase inhibitors) have improved overall patient survival, up to ~40% of luminal breast tumors eventually progress to ER+, but endocrine-resistant disease. Therefore, there is a critical need to delineate the processes driving ER+ breast cancer progression and identify new biomarkers that can be targeted in combination with ER-targeted therapies. An emerging biomarker of increased breast cancer risk and aggressive tumor behavior is oncogenic PELP1 (i.e., partially localized to the cytoplasm; cyto PELP1). PELP1 is typically located in the nucleus in normal breast tissue; however, partial to complete localization of PELP1 to the cytoplasm has been observed in up to 50% of PELP1+ breast tumors. Although a number of studies have implicated oncogenic PELP1 in luminal breast cancer biology, the mechanisms underlying oncogenic PELP1 actions in cancer remain poorly defined. To elucidate the impact of oncogenic PELP1 on steroid hormone receptor (SR) signaling pathways and transcription programs, we generated SR+ breast cancer cell models expressing vector control, wild-type (nuclear) PELP1, and oncogenic (cyto) PELP1. Herein, we identified AIB1 (amplified in breast cancer 1; ER coactivator) as a preferential binding partner of oncogenic PELP1. In particular, our data demonstrate that oncogenic PELP1 overexpression increases activation (i.e., phosphorylation) of AIB1, enhances tumorsphere formation in SR+ breast cancer models, and upregulates specific target genes identified through RNA-Seq analysis that are related to cell survival, breast cancer progression, and stem/progenitor formation independent of hormone stimulation. Knockdown of AIB1 inhibits oncogenic PELP1-induced tumorsphere formation and downregulates oncogenic PELP1 target genes. Moreover, knockdown of PELP1 in AIB1-mouse derived tumor cells results in decreased tumor growth in vivo. To our knowledge, our findings are the first to directly link oncogenic PELP1-induced phenotypes to AIB1 in breast cancer. Our studies suggest that directly targeting PELP1 may halt tumor progression, particularly in the context of AIB1-mediated tumorigenesis. Taken together, our data highlight the oncogenic PELP1/AIB1 interaction as an important hormone-independent mechanism of increased breast tumor cell survival and altered cell fate, and as an important mediator of disease progression. In sum, we conclude that oncogenic PELP1 and AIB1 could be used as biomarkers in conjunction with each other to identify breast cancer patients likely to respond to therapeutic strategies designed to selectively target PELP1, AIB1, or the oncogenic PELP1/AIB1 signaling and transcriptional complex. Citation Format: Thu H. Truong, Hsiangyu Hu, Julie H. Ostrander, Carol A. Lange. PELP1 and AIB1 cooperate to promote breast cancer progression in ER+ breast cancer models [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A30.