Abstract A32: Cell dormancy and tumorigenicity due to PTEN loss

Breast cancer is the most frequent malignancy in women, and although many breast cancers are curable via surgery, approximately one quarter maintain a latent and insidious characteristic of slow growth with early metastasis. The loss of the tumor suppressor PTEN is associated with breast cancer stage, increased lymph node status, and disease-related death, and the high rate of loss in primary tumors suggests a potential role in initiation and/or progression of the disease. However, specific cellular alterations in human breast epithelium controlled by PTEN inactivation, which lead to an increased metastatic phenotype, remain poorly defined. Many breast cancers have an activated PI3K pathway either due to PTEN loss or PI3K mutation, while a large fraction of breast tumors carry oncogenic mutations that cause hyperactivation of the MAPK/ERK cascade (20%–25% ErbB2, 5% KRAS, 2% BRAF, 1% HRAS, 1% NRAS). Using the isogenic non-tumorigenic MCF-10A and MCF-10A PTEN-/- cells, we have determined that PTEN-/- cells persist in mouse xenografts while their isogenic counterparts disappear. Although the PTEN-/- cells form small, 2mm tumors, these cells do not produce large growths. Since the current view of cancer is based on a “multi-hit” hypothesis: human cancers display a multitude of genetic and epigenetic changes, and a number of such alterations are required for the step-wise progression of tumor development, the activation of both signaling pathways may cooperate to promote tumorigenesis. We therefore tested the hypothesis that the activation of the MAPK pathway in a PTEN-negative background promotes tumorgenicity. To determine the cooperativity of PTEN loss and the MAPK pathway, we have expressed activated KRAS(V12) in the MCF-10A PTEN-/- cells. The combination of PTEN loss and KRas(V12) expression resulted large tumors within 4 weeks of injection. Interestingly, we discovered that “one-hit” of either PTEN loss or active Ras leads to a cellular persistence in vivo, a characteristic that may have been previously overlooked in more genetically unstable tumor cells. Citation Format: Keyata N. Thompson, Rebecca A. Whipple, Monica S. Charpentier, Amanda E. Boggs, Lekhana Bhandray, Kristi R. Chakrabarti, Stuart S. Martin, Michele I. Vitolo. Cell dormancy and tumorigenicity due to PTEN loss. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 20