Abstract 3996: Liquid to solid: Leukemic breast tumors assume the morphologic and genetic characteristics of breast cancer
Authors: Cunningham Isabel , Hamele-Bena Diane , Shiomi Takayuki , Emerson Stephen , Silva Jose M. , D'Armiento Jeanine M. , Weeraratna Ashani T. 
Published: May 2015

Chemoresistance is responsible for death in up to 60% of acute leukemia patients despite high initial responses to therapy; a new approach to residual disease is crucial. Leukemia is considered a liquid cancer that circulates through organs and homes to the marrow niche. It sometimes adopts, however, a solid tumor phenotype in an extramedullary organ, an under-investigated means of developing resistance. Solid masses grow and progress to invade other organs regardless of marrow involvement. Occult, sub-clinical, resistant foci may occur more often than is recognized, and lead to marrow relapse and death. Scans and autopsies are rarely performed and only obvious tumors are reported, so the incidence of resistant masses is unknown. We observed that leukemic tumors in breast assume the aggressive phenotype of invasive lobular breast cancer, with similar morphologic features (single-filing and targetoid pattern), and metastasize to the same organs. AML and ALL tumors bear leukemic markers and are cytokeratin-, hormone receptor-, and e-cadherin negative. Only 4 of 106 reported cases treated with only chemotherapy survived 4 years, but when tumor excision was added, leukemia-free survival over 20 years has occurred (Am J Hem, 2012). Based on these observations, we postulate that understanding the molecular mechanisms that regulate these solid masses would be a potential means to overcome the chemoresistance that prevents cure in AML and ALL. Gene expression profile studies were performed on paraffin-fixed leukemic breast tumors (2 ALL, 1 AML) found 8 to 22 months after diagnosis while marrows remained in remission. Many of the same genes were significantly upregulated in leukemic tumors (30 to 2877-fold) and breast cancer (9 to 108-fold). The most enriched clusters by DAVID analysis were actin cytoskeleton organization, cell cycle, and regulation of apoptosis. RhoGTPases were significantly upregulated in both types, as was PI3Kδ. Among genes related to metastasis in breast (and other) cancers, some (PTTG1, ELMO1, VAV1, PAK1, NEK2) were upregulated 5 to 224 times in leukemic tumors. Profilin, KLF6, and CXCL14 were significantly downregulated in both leukemic and epithelial tumors, as were cell cycle regulators CDKN1A, CDKN1B, and cyclin D2. Wiskott-Aldrich Syndrome gene, known to correlate with resistance in AML and ALL, was significantly upregulated in leukemic tumors and carcinomas. Overall, the results indicate a remodeling of the cytoskeleton, promotion of metastasis, and a decrease in cell cycle regulation in the leukemic tumors. Studies with 25 leukemic breast tumors are ongoing to identify key aberrant gene targets. Characterizing the dysregulation responsible for transformation to a tumor phenotype has the potential to lead to specific agents. These could be used in conjunction with marrow-effective leukemia drugs to eradicate resistant foci to cure more acute leukemias.

Citation Format: Isabel Cunningham, Diane Hamele-Bena, Takayuki Shiomi, Stephen Emerson, Jose M. Silva, Jeanine M. D'Armiento, Ashani T. Weeraratna. Liquid to solid: Leukemic breast tumors assume the morphologic and genetic characteristics of breast cancer. [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 3996. doi:10.1158/1538-7445.AM2014-3996