PIK3CA mutations and TP53 alterations cooperate to increase cancerous phenotypes and tumor heterogeneity

Sarah Croessmann, Hong Yuen Wong, Daniel J. Zabransky, David Chu, D. Marc Rosen, Justin Cidado, Rory L. Cochran, William Dalton, Bracha Erlanger, Karen Cravero, Berry Button, Kelly Kyker-Snowman, Paula Hurley, Josh Lauring, Ben Ho Park

Research output: Contribution to journalArticle

Abstract

Background/purpose: The combined contributions of oncogenes and tumor suppressor genes toward carcinogenesis remain poorly understood. Elucidation of cancer gene cooperativity can provide new insights leading to more effective use of therapies. Experimental design/Methods: We used somatic cell genome editing to introduce singly and in combination PIK3CA mutations (E545K or H1047R) with TP53 alterations (R248W or knockout), to assess any enhanced cancerous phenotypes. The non-tumorigenic human breast epithelial cell line, MCF10A, was used as the parental cell line, and resultant cells were assessed via various in vitro assays, growth as xenografts, and drug sensitivity assays using targeted agents and chemotherapies. Results: Compared to single-gene-targeted cells and parental controls, cells with both a PIK3CA mutation and TP53 alteration had increased cancerous phenotypes including cell proliferation, soft agar colony formation, aberrant morphology in acinar formation assays, and genomic heterogeneity. Cells also displayed varying sensitivities to anti-neoplastic drugs, although all cells with PIK3CA mutations showed a relative increased sensitivity to paclitaxel. All cell lines remained non-tumorigenic. Conclusions: This cell line panel provides a resource for further elucidating cooperative genetic mediators of carcinogenesis and response to therapies.

Original languageEnglish (US)
Pages (from-to)1-14
Number of pages14
JournalBreast Cancer Research and Treatment
DOIs
StateAccepted/In press - Feb 11 2017

Keywords

  • Breast cancer
  • PIK3CA
  • TP53
  • Tumor heterogeneity

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Croessmann, S., Wong, H. Y., Zabransky, D. J., Chu, D., Rosen, D. M., Cidado, J., Cochran, R. L., Dalton, W., Erlanger, B., Cravero, K., Button, B., Kyker-Snowman, K., Hurley, P., Lauring, J., & Park, B. H. (Accepted/In press). PIK3CA mutations and TP53 alterations cooperate to increase cancerous phenotypes and tumor heterogeneity. Breast Cancer Research and Treatment, 1-14. https://doi.org/10.1007/s10549-017-4147-2