Dimri G, Band H, Band V.. Mammary epithelial cell transformation: insights from cell culture and mouse models. Breast Cancer Res 7: 171-179

Division of Cancer Biology, Department of Medicine, ENH Research Institute, Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Evanston, Illinois, USA.
Breast cancer research: BCR (Impact Factor: 5.49). 02/2005; 7(4):171-9. DOI: 10.1186/bcr1275
Source: PubMed


Normal human mammary epithelial cells (HMECs) have a finite life span and do not undergo spontaneous immortalization in culture. Critical to oncogenic transformation is the ability of cells to overcome the senescence checkpoints that define their replicative life span and to multiply indefinitely -- a phenomenon referred to as immortalization. HMECs can be immortalized by exposing them to chemicals or radiation, or by causing them to overexpress certain cellular genes or viral oncogenes. However, the most efficient and reproducible model of HMEC immortalization remains expression of high-risk human papillomavirus (HPV) oncogenes E6 and E7. Cell culture models have defined the role of tumor suppressor proteins (pRb and p53), inhibitors of cyclin-dependent kinases (p16INK4a, p21, p27 and p57), p14ARF, telomerase, and small G proteins Rap, Rho and Ras in immortalization and transformation of HMECs. These cell culture models have also provided evidence that multiple epithelial cell subtypes with distinct patterns of susceptibility to oncogenesis exist in the normal mammary tissue. Coupled with information from distinct molecular portraits of primary breast cancers, these findings suggest that various subtypes of mammary cells may be precursors of different subtypes of breast cancers. Full oncogenic transformation of HMECs in culture requires the expression of multiple gene products, such as SV40 large T and small t, hTERT (catalytic subunit of human telomerase), Raf, phosphatidylinositol 3-kinase, and Ral-GEFs (Ral guanine nucleotide exchange factors). However, when implanted into nude mice these transformed cells typically produce poorly differentiated carcinomas and not adenocarcinomas. On the other hand, transgenic mouse models using ErbB2/neu, Ras, Myc, SV40 T or polyomavirus T develop adenocarcinomas, raising the possibility that the parental normal cell subtype may determine the pathological type of breast tumors. Availability of three-dimensional and mammosphere models has led to the identification of putative stem cells, but more studies are needed to define their biologic role and potential as precursor cells for distinct breast cancers. The combined use of transformation strategies in cell culture and mouse models together with molecular definition of human breast cancer subtypes should help to elucidate the nature of breast cancer diversity and to develop individualized therapies.

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    • "In vitro manipulation of HMECs has served as a useful strategy to understand the molecular mechanisms of breast cell transformation (Dimri et al., 2005). For example, introduction of HPV E6 and E7 into primary HMECs led to their immortalization (Wazer et al., 1995; Gudjonsson et al., 2002). "

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    • "The mammary gland consists of a branching ductal system that ends in terminal ducts known as ductal-lobular units (TDLUs) and an interlobular matrix consisting of fat and fibrous tissues that represent the extracellular matrix (ECM) of adipocytes and stromal fibroblasts [1]. Most breast cancers arise in the ductal-lobular units that are characterized by the presence of a basement membrane and luminal, myoepithelial , and progenitor/stem cells [1] [2] [3]. Progression of the ductal hyperproliferation involves the in situ and invasive carcinoma and finally the metastasis. "
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    ABSTRACT: Collagen VI and hyaluronan are widely distributed extracellular matrix macromolecules that play a crucial role in tissue development and are highly expressed in cancers. Both hyaluronan and collagen VI are upregulated in breast cancer, generating a microenvironment that promotes tumour progression and metastasis. A growing number of studies show that these two molecules are involved in inflammation and angiogenesis by recruiting macrophages and endothelial cells, respectively. Additionally, collagen VI induces epithelial-mesenchymal transition that is correlated to increased synthesis of hyaluronan in mammary cells. Hyaluronan has also a specific role in cellular functions that depends mainly on the size of the polymer, whereas the effect of collagen VI in tumour progression may be the result of the intact molecule or the C5 peptide of α 3(VI) chain, known as endotrophin. Collectively, these findings strongly support the parallel role of these molecules in tumour progression and suggest that they may be used as prognostic factors for the breast cancer treatment.
    BioMed Research International 07/2014; 2014(2):606458. DOI:10.1155/2014/606458 · 1.58 Impact Factor
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    • "After obtaining informed consent, a 10 gauge core needle was used to obtain breast tissue (<100 mg) from 39 healthy female volunteers with no history of breast disease (see Additional file 1: Table S1 for age, race, and Gail risk score) [8]. The tissue was immediately homogenized, digested with collagenase and hyaluronidase, and cultured using selective media and trypsinization to differentiate the epithelial cells from stromal cells as previously described [17-21]. The KTB HME cells (K-HME; K-HME 490, K-HME 509, K-HME 538, K-HME 496, and K-HME 511) were obtained from frozen stocks, thawed, and suspended in WIT-P media (Stemgen, San Diego, CA, USA) unless otherwise stated (see Additional file 2: Methods) then plated onto Primaria-coated T-25 flasks (BD Bioscience, San Jose, CA, USA). "
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    ABSTRACT: Background Normal, healthy human breast tissue from a variety of volunteer donors has become available for research thanks to the establishment of the Susan G. Komen for the Cure® Tissue Bank at the IU Simon Cancer Center (KTB). Multiple epithelial (K-HME) and stromal cells (K-HMS) were established from the donated tissue. Explant culture was utilized to isolate the cells from pieces of breast tissue. Selective media and trypsinization were employed to select either epithelial cells or stromal cells. The primary, non-transformed epithelial cells, the focus of this study, were characterized by immunohistochemistry, flow cytometry, and in vitro cell culture. Results All of the primary, non-transformed epithelial cells tested have the ability to differentiate in vitro into a variety of cell types when plated in or on biologic matrices. Cells identified include stratified squamous epithelial, osteoclasts, chondrocytes, adipocytes, neural progenitors/neurons, immature muscle and melanocytes. The cells also express markers of embryonic stem cells. Conclusions The cell culture conditions employed select an epithelial cell that is pluri/multipotent. The plasticity of the epithelial cells developed mimics that seen in metaplastic carcinoma of the breast (MCB), a subtype of triple negative breast cancer; and may provide clues to the origin of this particularly aggressive type of breast cancer. The KTB is a unique biorepository, and the normal breast epithelial cells isolated from donated tissue have significant potential as new research tools.
    BMC Cell Biology 06/2014; 15(1):20. DOI:10.1186/1471-2121-15-20 · 2.34 Impact Factor
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