Abstract
Two-thirds of breast cancers express estrogen receptor alpha (ERα) and are estrogen-dependent for growth, yet the unavailability of accurate in vivo models has long impeded the characterisation of critical events that lead to the development of these luminal subtypes of the disease. Previously, our group successfully created an ERα-positive breast cancer model by quantitative transformation of normal human mammary epithelial cells (HMECs) derived from reduction mammoplasties. HMECs were grown as mammospheres in suspension to enrich for progenitor cells, which were then transformed using lentiviral vectors encoding ERα and TERT as well as the polycomb gene BMI1 and MYC, both of which have been implicated in ERα-positive breast cancer. Injection of transformed HMECs into mammary fad pads of NOD/SCID mice resulted in the formation of estrogen-dependent tumours that metastasised to multiple organs [1], confirming the creation of a model that mirrors the characteristics of human estrogen-dependent breast cancer. Somewhat surprisingly, we observed islands of squamous differentiation in the tumours that formed in the NOD/SCID mice, whereas the large majority of human breast tumours are adenocarcinomas. To address this discrepancy, we are currently testing a combination of our established protocol with new HMECs in vitro culture conditions that have recently been shown to abrogate the squamous phenotype of the resulting tumours in mice [2]. Our model system is a powerful tool for the in vivo characterisation of candidate genes that have been implicated in development of ERα-positive breast cancer. Genes of interest include TNRC9, which has recently been identified in genome-wide association studies as a potential novel breast cancer susceptibility gene [3], as well as TBX3, which is known to play a role in mammary gland development as well as breast tumourigenesis. We are currently testing these genes in our model using overexpression and knockdown approaches.
Highlights
Obesity will soon be the leading preventable risk factor for many cancers
Previous epidemiological studies have investigated the relationship between individual nutrients such as vitamin D and O3 vitamin B12 and mammographic density, a strong marker of breast cancer risk [1], with varied results
We examine prospective data to determine A Bensmail, I Hutcheson, M Giles, J Gee, R Nicholson whether dietary patterns from childhood to adult life affect Tenovus Centre for Cancer Research, Welsh School of Pharmacy, mammographic density
Summary
Obesity will soon be the leading preventable risk factor for many cancers. The insulin-like growth factors (IGFs) have been strongly implicated as important risk factors for many epithelial cancers, including breast cancer, and for mediating the link between nutrition and these cancers. Overexpression of 15-PGDH partially restored sensitivity of TAMr cells to 4-hydroxytamoxifen by the MTT assay, demonstrating that 15-PGDH downregulation plays a functional role in the acquisition of TAMr. Treatment of TAMr MCF-7 cells with a DNA methyltransferase inhibitor (5-azacytidine), and a histone deacetylase inhibitor (trichostatin A), led to re-expression of 15-PGDH mRNA (by quantitative RT-PCR), suggesting that 15-PGDH is silenced via epigenetic mechanisms during the acquisition of TAMr. To address whether 15-PGDH downregulation is involved in clinical TAMr, we assembled a tissue microarray comprising 89 relapsed primary human breast cancers and 234 tamoxifen-sensitive controls. Oestrogen receptor-positive breast cancers develop resistance to anti-oestrogens by utilising alternative growth factor pathways as observed in our tamoxifen-resistant cell line (TAMR) These include EGFR, IGF1-R and Src signalling as well as increased growth and invasion. The tumour size was followed by regular measurement with calipers
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