Dr Matt Smalley
Breast cancer is a highly heterogeneous disease. That heterogeneity is found both as inter- and intra-tumour heterogeneity. Inter-tumour heterogeneity can be classified on the basis of clinical parameters (e.g. grade, expression of hormone receptors), gene expression profiling and/or histological description (there are more than 20 different histological subtypes of breast cancer) and the biological basis for this heterogeneity is largely unknown. If we can understand this, we will not only have a better understanding of the basic biology of tumour development but it will also lead to better patient stratification and the development of targeted therapies for specific tumour subtypes.
Intra-tumour heterogeneity is shown by the multitude of different cell types found within a tumour. These can be described in terms of their appearance, e.g. epithelioid, spindle cells (EMT-like), squamoid, but also functionally. The most important of these functional classifications is into cells which possess stem cell-like features and cells which do not. Tumour cells which possess stem cell-like features (‘cancer stem cells’ or CSCs) may be responsible for maintaining the primary tumour as well as for seeding of metastases. Importantly, evidence is emerging that these functional populations may not have fixed identities but may be able to interconvert. Thus, if stem cell-like functions are to be targeted as a therapeutic strategy, it may be necessary to not only kill CSCs already present in the tumour but to block to conversion of non-CSCs to CSCs. One of the ways tumours may acquire stem cell-like functions is to re-activate and/or deregulate biological processes / signalling networks associated with normal stem/progenitor cells.
We are working with mouse models of breast cancer to address these issues. We are investigating how the same genetic lesions occurring in different stem/progenitor cells of origin can affect breast cancer heterogeneity. Conversely, we are studying how making different lesions in the same cell of origin activates different signalling networks to generate different tumour phenotypes. We have demonstrated that loss of the Brca1 tumour suppressor gene in luminal epithelial progenitors in the mammary gland, and not in basal stem cells, gives rise to tumours which phenocopy human BRCA1 breast cancers and the majority of non-familial basal-like breast cancers (Molyneux et al, Cell Stem Cell, 2010). We are now working with different combinations of Pten, Brca1, Brca2, p53 and Her2/Neu conditional alleles together with promoters that target basal stem cells, luminal estrogen receptor negative or luminal estrogen receptor positive cells.
Brca1 GEMM tumour. A, B) Low (bar = 4mm) and medium power (bar = 270 um) H+E images. C) Keratin 14 staining. D) Keratin 18 staining. Bar (C, D) = 270 um.
We are also identifying key processes involved in regulation of normal mammary stem/progenitor cell behaviour. Following on from our detailed molecular analysis of mammary epithelial cell subpopulations (Kendrick et al, 2008), we identified the c-Kit signalling network as a regulator of mammary progenitor survival and proliferation (Regan et al, Oncogene, 2011). We also found that the Src family kinase Lyn, a downstream transducer of c-Kit signalling, is expressed in normal mammary progenitors and over-expressed in basal-like breast cancers (Molyneux et al, Cell Stem Cell, 2010; Regan et al, Oncogene, 2011). We are currently examining how Lyn deregulation may promote breast cancer formation and whether it is potential therapeutic target in this cell type.
Our expertise in isolation of mammary cell subpopulations (Sleeman et al, Breast Cancer Research, 2006; Sleeman et al, J Cell Biol, 2007; Britt et al, Breast Cancer Research, 2009; Regan et al, Oncogene, 2011) has enabled us to purify mammary stem cells away from other mammary cell populations, including other basal cell types, and carry out molecular profiling. We have identified a number of genes specifically expressed in the mammary stem cells and we are currently assaying them for their function in the biology of the normal mammary gland. If the genes are found to have important roles in the function of the normal stem cells, we will go on to determine whether their activity is deregulated in cancer stem cells and whether they have potential as therapeutic targets.
Wholemount of mammary fat pad transplanted with primary mammary epithelial cells transduced ex vivo with a lentivirus expressing GFP. Bar = 225 um.
Current Grant Support
CR-UK Programme Grant
Breast Cancer Campaign Project Grant
EU Innovative Medicines Initiative Consortium PREDECT
Professor Keith Brennan (University of Manchester)
Professor Jorge Reis-Filho (Memorial Sloan-Kettering, New York)
Dr Beatrice Howard (Institute of Cancer Research, London)
Dr Mohamed Bentires-Alj (Friedrich Miescher Institute, Basel)
Dr Emma Davies