Jane Visvader - Defining the Cellular Culprits Underlying Breast Cancer

Figure 1.  Simplified model of the arrangement of cells along a hierarchy in the mammary gland, with adult breast stem cells sitting at t...

Figure 1.  Simplified model of the arrangement of cells along a hierarchy in the mammary gland, with adult breast stem cells sitting at the apex of the hierarchy. Gene expression correlations have pointed to possible relationships between normal breast epithelial cells and the major subtypes of breast cancer. For example, the luminal progenitor daughter cell is the likely target cell for aggressive basal-like cancers. The image is taken from Visvader, Genes and Development, 2009.
Breast cancer is the end result of a step-wise accumulation of genetic mutations that first arise in normal breast tissue. In many ways, breast tumours should be viewed as a caricature of normal breast development that has gone awry. Breast cancer is now known to be a highly heterogeneous disease, likely reflecting its origins in the different cell types that make up normal ductal tissue in the breast. From this perspective, tumour heterogeneity represents abortive attempts by cancer cells to undergo normal growth and maturation. In order to tackle the question of this heterogeneity and to design more effective ‘personalized’ therapies, it is essential to understand the normal cell types that constitute breast ductal tissue and to understand how specific genetic mishaps give rise to cancer.

Integral to the development of every organ is a hierarchy of cells that produce the full repertoire of mature cells in that organ. In breast tissue, there are three distinct cell types that constitute the mammary ductal tree: the inner layer of luminal cells, alveolar cells (milk-producing cells in lactation) and an outer sleeve of myoepithelial cells. In contrast to other organs that form in utero, mammary gland development is largely a post-natal event and hence the majority of these cells are produced during puberty and adulthood. During puberty, ductal branching and elongation result in a complex network of ducts that fill the entire mammary fat pad. Massive expansion of the tissue also accompanies pregnancy, when milk-secretory alveolar structures develop and differentiate to produce milk for lactation. The capacity to physically isolate distinct cell subpopulations from both normal tissue and breast cancers (a relatively new capability) has enabled researchers to tackle the issue of cancer heterogeneity and to specifically ask which ductal cell type is the initial target for transformation into a cancer cell. Stem cells lie at the apex of the normal tissue hierarchy and give rise to a variety of daughter cells, which then yield mature ductal cells (Figure 1). Stem cells represent strong candidates for ‘cells of origin’ in breast cancer since they are long-lived and are capable of extensive self-renewal (making perfect copies of themselves). Therefore, these cells have greater potential to acquire the multiple genetic mishaps that characterise cancer. Daughter cells may also serve as ‘cells of origin’ in cancer as their highly proliferative nature would impart potent growth properties to a rogue cancer cell.

The breast stem cell hierarchy

Over the past decade, our team has identified and isolated breast stem cells from mouse and human mammary tissue through flow cytometry combined with transplantation studies. Importantly, analogous findings were made by a Canadian group. Further fractionation studies led to the isolation of distinct types of daughter cells (the progeny of stem cells). Striking functional and molecular similarities (based on gene expression signatures) were found between stem cells and their progeny in human and mouse tissue, with a number of conserved pathways unveiled. In parallel studies, we defined master transcriptional regulators of self-renewal, cell-fate and differentiation, that act at specific phases of breast development. Many of these molecules are deregulated in cancer, thus lending support to the notion that perturbation of key developmental regulators can lead to cancer. In exciting recent work that employs novel 3D imaging technology to visualise large portions of intact breast tissue, we have performed lineage tracing studies to track stem and progenitor cells in situ (Figure 2). Based on this technology, stem cells were found to be very long-lived, suggesting that they are prime candidates for breast cancers that can arise many decades after incurring a genetic mutation.

The purification strategy has not only made it possible for us to view breast cancer through the prism of stem cell biology, but has shed light on how female hormones regulate breast stem cells and cancer risk. The mammary epithelium is highly sensitive to the effects of the ovarian steroid hormones oestrogen and progesterone, which are integral to puberty, oestrus cycling and pregnancy. The receptors for these nuclear steroid hormones (ERα and PR) remain critical prognostic markers in breast cancer. To understand potential cellular mechanisms that contribute to the strong epidemiological link between sustained hormone exposure and increased breast cancer risk, we turned to analysis of the cellular hierarchy. Our studies revealed that MaSCs were exquisitely responsive to steroid hormones, despite the lack of expression of ERα and PR on these cells, thus invoking an indirect (paracrine) mechanism of action. RANK ligand was identified as a paracrine regulator of signalling from progesterone responsive ductal cells to breast stem cells. These findings highlighted the RANK pathway as a potential target for breast cancer prevention.

Breast tumours and the ‘cells of origin’ of cancer

Breast cancer is a very heterogeneous disease at both the histological and molecular levels. At least six distinct subtypes have been described on the basis of gene expression profiling, with the most important determinants of these subtypes being the presence or absence of expression of the oestrogen receptor (ER), progesterone receptor (PR) or the amplification/overexpression of the HER2/ERBB2 locus (Figure 1). Despite the ability of these subtypes to predict outcome, patient response to chemotherapy or targeted therapy remains variable. The prevailing concept in the field has been that these different subtypes originate in distinct breast epithelial cells that serve as the ‘cell of origin’. A better understanding of breast tumour heterogeneity and the nature of tumour-propagating cells requires definition of epithelial cells in normal breast tissue. This is particularly relevant to women at high risk of developing breast cancer such as those carrying germ-line mutations in specific tumour suppressor genes.

Through analysis of precancerous tissue isolated from women that carry a mutation in the critical BRCA1 tumour suppressor gene (the ‘Angelina Jolie gene’) and who have an increased risk of developing aggressive breast cancers, we discovered that an aberrant population of daughter cells is highly prone to carcinogenesis. The identification of cells in which cancer originates should help highlight key genetic vulnerabilities of the cancer cell that could be used to develop more refined therapeutic targets to tailor therapy to distinct tumour subtypes. A number of genetic pathways have now been identified for exploring new treatment strategies aimed at switching off breast tumour growth.

Figure 2. 3D confocal wholemount images of mammary glands before puberty (upper panel) and in the adult (lower panel). The top panel shows the primitive ductal tree evident before puberty (inset shows elongated cells in the outer layer), while the lower panel depicts clones of cells (along the ductal tree) that have likely arisen from single stem cells that expanded in vivo for 8 weeks. Note the yellow and red domains that depict clonal areas. Images are taken from Rios et al Nature 2014.

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2015 2016 biography Biological Sciences biomaterials biomedicine bionics Bionics Institute biotechnology breast cancer cancer cartography Ecological Management Ecology endocrinology epidemiology exploration Flinders University Forest Management Forest Science genetic mutation Gillian Dooley Hugh McDermott hydrography implants James Fallon Jane Visvader Matthew Flinders medicine multidisciplinary naval history navigation neural prosthesis prosthetics Research Spotlight Robert Shepherd science history stem cells surgery treatment University of Melbourne Zoology
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TRANSACTIONS: Jane Visvader - Defining the Cellular Culprits Underlying Breast Cancer
Jane Visvader - Defining the Cellular Culprits Underlying Breast Cancer
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