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Tan, Susanna Shu Xian

University of British Columbia

Human breast cancers are well recognized for their genetic and biologic heterogeneity but are, nevertheless, usefully classified into subgroups that guide their treatment. Unfortunately, those now identified as highly proliferative ER-, PR- and HER2-negative cancers (i.e., “triple-negative”, TNBCs) remain generally incurable and hence are in particular need of new strategies to design and test targeted treatments. The ultimate goal of this project was to create a reproducible human model of TNBCs by building on a previous de novo experimental design that consistently produces variably ER-, PR- and HER2-positive human invasive ductal breast carcinomas, from either of two types of EGF-responsive normal human mammary cells, transduced with a KRASᴳ¹²ᴰ(K)-encoding vector prior to being transplanted into adult immunodeficient mice. However, although self-sustaining, these tumours do not expand after the first 4-6 weeks post-transplant. Interestingly, experiments designed to determine whether two candidate extrinsic modifiers, human hepatocyte growth factor and a diet-induced obese environment, might enhance the growth of the K-induced tumours, failed to reveal any evidence of such an effect. In contrast, the concurrent overexpression of BMI1, MYC and TP53ᴿ²⁷³ᶜ with K (KBMT) in human mammary cells showed that within a week, transplants of these cells already contained an increased frequency of Ki67+ cells and subsequently produced still YB-1-dependent, but now continuously expanding TNBCs. Transduction with KRASᴳ¹²ᴰ was required for any tumours to form from this collection of potential oncogenic drivers, although variable outputs were obtained when any of the BMI1, MYC, or TP53ᴿ²⁷³ᶜ oncogenes were omitted. FACS analyses showed the surface marker phenotypes of the cells present in these rapidly growing tumours to be remarkably homogeneous, with features of normal basal cells. In addition, despite any evidence of metastatic capability detected in vivo, cells isolated from all KBMT-induced tumours tested could be expanded in vitro and generated fast growing tumours in secondary mice. These findings demonstrate the feasibility of rapidly and reproducibly creating a model of human TNBC de novo from initially normal mammary cells, thus offering a new and powerful platform for potentially developing novel prevention, diagnostic, as well as treatment approaches applicable to this disease.

Text

2022-12-21

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/83453

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/