Alterations of EGFR, p53 and PTEN that mimic changes found in basal-like breast cancer promote transformation of human mammary epithelial cells

Abstract

Breast cancer can be classified into different molecular subtypes with varying clinical and pathological characteristics. The basal-like breast cancer subtype represents one of the most aggressive and lethal types of breast cancer, and due to poor mechanistic understanding, it lacks targeted therapy. Many basal-like breast cancer patient samples display alterations of established drivers of cancer development, including elevated expression of EGFR, p53 inactivating mutations and loss of expression of the tumor suppressor PTEN; however, their contribution to human basal-like breast cancer pathogenesis remains ill-defined. Using non-transformed human mammary epithelial cells, we set out to determine whether altering EGFR, p53 and PTEN in different combinations could contribute to basal-like breast cancer progression through transformation of cells. Altering PTEN in combination with either p53 or EGFR in contrast to any of the single alterations caused increased growth of transformed colonies in soft agar. Concomitantly modifying all three genes led to the highest rate of cellular proliferation and the greatest degree of anchorage-independent colony formation. Results from our effort to engineer a model of BBC expressing alterations of EGFR, p53 and PTEN suggest that these changes are cooperative and likely play a causal role in basal-like breast cancer pathogenesis. Consideration should be given to targeting EGFR and restoring p53 and PTEN signaling simultaneously as a strategy for treatment of this subtype of breast cancer.

Keywords: :

• basal-like breast cancer
• EGFR
• PTEN
• p53
• dominant-negative
• MCF10A
• oncogene
• tumor suppressor
• transformation
• soft agar

This article is referred to by:

The multi-hit hypothesis in basal-like breast cancer

Disclosure of Potential Conflicts of Interest

The authors have no conflict of interest or financial interest to disclose.

Acknowledgments

M.M.P. was awarded and supported by the Department of Defense Predoctoral Breast Cancer Traineeship Award (W81XWH-09–1-0045). This work was also supported by the following grants to R.E.P.: National Cancer Institute (P01CA97403), the Susan G. Komen for the Cure Foundation and The Manhasset Women’s Coalition Against Breast Cancer. We thank the members of the Parsons laboratory for helpful discussions and feedback, particularly Dr Megan Keniry. We thank Dr Marcos M. Pires (Lehigh University) for helpful discussions and help with the manuscript. We thank Dr Matthew Maurer and Dr Ying-ka Ingar Lau (Columbia University) for helpful discussions.