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

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  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

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.

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Author contributions

SC, BHP—Conception and design. SC, HYW, DJZ, RLC, WBD, PJH, JL, BHP—Development of methodology. SC, HYW, DJZ, JC, RLC, BE, BB, KC, KKS, PJH, JL, BHP—Acquisition of data. SC, HYW, DJZ, DC, DMR, JC, RLC, WBD, BE, KC, BBK-S, PJH, JL, BHP—Analysis and interpretation of data. SC, HYW, DJZ, DC, DMR, JC, RLC, WBD, BE, KC, BB, KK-S, PJH, JL, BHP—Writing, review, and/or revision of the manuscript.

Funding

This work was supported by: The Avon Foundation (B.H.P., J.L.), and NIH CA009071 (K.C., B.H.P.), GM007309 (D.J.Z.), CA168180 (R.L.C.), CA167939 (S.C.). We would also like to thank and acknowledge the support of NIH P30 CA006973, the Sandy Garcia Charitable Foundation, the Commonwealth Foundation, The Walsh Foundation, the Santa Fe Foundation, the Breast Cancer Research Foundation, the Health Network Foundation, the ME Foundation, the Augustine Fellowship (W.B.D.), and The Robin Page/Lebor Foundation. None of the funding sources influenced the design, interpretation, or submission of this manuscript.

Author information

Author notes

  1. Justin Cidado

    Present address: Oncology iMED, AstraZeneca, 35 Gatehouse Dr., Waltham, MA, 02451, USA

Authors and Affiliations

  1. The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, 1650 Orleans Street, Room 151, Baltimore, MD, 21287, USA

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

  2. Department of Chemical and Biomolecular Engineering, The Whiting School of Engineering, The Johns Hopkins University, Baltimore, MD, 21218, USA

    Ben Ho Park

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  1. Sarah Croessmann
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Corresponding author

Correspondence to Ben Ho Park.

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Conflict of interest

BHP is a paid member of the scientific advisory boards of Horizon Discovery, LTD, and Loxo Oncology, and has research contracts with Genomic Health, Inc and Foundation Medicine, Inc. Under separate licensing agreements between Horizon Discovery, LTD, and The Johns Hopkins University, BHP is entitled to a share of royalties received by the University on sales of products. The terms of this arrangement are being managed by the Johns Hopkins University, in accordance with its conflict of interest policies. All other authors declare no potential conflicts.

Ethical approval

All animal experiments were performed in accordance with institutional and the National Institutes of Health Guide for the Care and Use of Laboratory Animals guidelines. This article does not contain any studies with human participants performed by any of the authors.

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Croessmann, S., Wong, H.Y., Zabransky, D.J. et al. PIK3CA mutations and TP53 alterations cooperate to increase cancerous phenotypes and tumor heterogeneity. Breast Cancer Res Treat 162, 451–464 (2017). https://doi.org/10.1007/s10549-017-4147-2

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  • DOI: https://doi.org/10.1007/s10549-017-4147-2

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