Dissecting genetic requirements of human breast tumorigenesis in a tissue transgenic model of human breast cancer in mice

Abstract

Breast cancer development is a complex pathobiological process involving sequential genetic alterations in normal epithelial cells that results in uncontrolled growth in a permissive microenvironment. Accordingly, physiologically relevant models of human breast cancer that recapitulate these events are needed to study cancer biology and evaluate therapeutic agents. Here, we report the generation and utilization of the human breast cancer in mouse (HIM) model, which is composed of genetically engineered primary human breast epithelial organoids and activated human breast stromal cells. By using this approach, we have defined key genetic events required to drive the development of human preneoplastic lesions as well as invasive adenocarcinomas that are histologically similar to those in patients. Tumor development in the HIM model proceeds through defined histological stages of hyperplasia, DCIS to invasive carcinoma. Moreover, HIM tumors display characteristic responses to targeted therapies, such as HER2 inhibitors, further validating the utility of these models in preclinical compound testing. The HIM model is an experimentally tractable human in vivo system that holds great potential for advancing our basic understanding of cancer biology and for the discovery and testing of targeted therapies.cancer model ͉ human in mouse ͉ tissue reconstitution

Presence of an in situ component is associated with reduced biological aggressiveness of size-matched invasive breast cancer

“…Such a model is reminiscent of colorectal cancer that may arise either through a polyp-dependent (adenoma carcinoma) process, or through a non-polyp-dependent (de novo) pathway associated with greater invasive and metastatic potential (Tanaka, 2009). In preclinical models of breast cancer, disruption of the TP53 pathway and/or constitutive activation of HER2, FAK or KRAS produce DCIS, but further inhibition of pRb signalling and/ or activation of the phosphatidylinositol 3 0 -kinase pathway appear necessary to promote malignant progression (Lightfoot et al, 2004;Golubovskaya et al, 2009;Wu et al, 2009). Comparative genomic hybridisation studies have also identified genetic pathways -for example through loss of genetic material of 16q associated with well-differentiated to intermediately differentiated DCIS and grade 1 IDC, or gains of 8q, 17q, and 20q associated with poorly differentiated DCIS and grade 3 IDC (Buerger et al, 2001) -that support a linear progression model for the transition from normal to DCIS to IDC.…”

Role of cancer-associated fibroblasts in breast cancer development and prognosis

“…Furthermore, ectopic expression of HGF and/or TGF-b in mouse fibroblasts before the implantation of ostensibly normal human mammary epithelial cells resulted in the outgrowth of benign and malignant lesions in the humanized fat pads of NOD/SCID mice (Kuperwasser et al, 2004;Wu et al, 2009). This suggests an important role of stromal fibroblast TGF-b in promoting breast carcinogenesis (Fig.…”

Tissue Recombination Models for the Study of Epithelial Cancer

“…Using primary, noncancerous human epithelial cells, several human-in-mouse models of skin carcinoma, melanoma, and breast cancer have been developed in a similar fashion to study the cellautonomous roles of oncogenic events (Fan et al 1997;Khavari 2006;Wu et al 2009). In addition, microenvironmental influences in carcinogenesis have also been examined in a human mammary reconstitution system, where the mouse MFP of SCID mice is "humanized" by introducing human mammary fibroblasts, thus facilitating proper colonization and growth of human mammary epithelial cells in the chimeric stroma (Kuperwasser et al 2004).…”