Abstract
Lineage tracing studies have become a well-suited approach to reveal cellular hierarchies and tumor heterogeneity. Cellular heterogeneity, particularly in breast cancer, is still one of the main concerns regarding tumor progression and resistance to anti-cancer therapies. Here, we review the current knowledge about lineage tracing analyses that have contributed to an improved comprehension of the complexity of mammary tumors, highlighting how targeting different mammary epithelial cells and tracing their progeny can be useful to explore the intra- and inter-heterogeneity observed in breast cancer. In addition, we examine the strategies used to identify the cell of origin in different breast cancer subtypes and summarize how cellular plasticity plays an important role during tumorigenesis. Finally, we evaluate the clinical implications of lineage tracing studies and the challenges remaining to address tumor heterogeneity in breast cancer.
Highlights
Thistype type cancer originates in the mamfrom the the World of of cancer originates in the mammary mary gland, which is a ductal tree composed of two epithelial compartments: cells facing gland, which is a ductal tree composed of two epithelial compartments: cells facing the the ductal lumen called luminal cells (LCs), and basal cells (BCs) found in the outer ductal lumen called luminal cells (LCs), and basal cells (BCs) found in the outer layerlayer with with a capacity to contract, which includes basal progenitor terminal differentia capacity to contract, which includes basal progenitor cellscells andand terminal differentiated ated myoepithelial
Luminal cells can further subdivided into two independent subpopsubpopulations based on the expression of the hormone receptor, estrogen receptor alpha ulations based on the expression of the hormone receptor, estrogen receptor alpha (ERα)
Some groups have used this technology to explore the capacity of different mammary epithelial cells to initiate tumors or metastasize, as well as to understand the potential mechanisms underlying cellular plasticity within breast tumors, which could lead to new therapeutic strategies for treating heterogeneous tumors in the near future
Summary
Breast cancer cancer isis the the most most common common cancer cancer in in women women worldwide worldwideand andisis the the second second leading leading cause cause of of cancer cancer death death in in women, women, exceeded exceededonly onlyby bylung lungcancer cancer(based Activated rtTA will bind to tetracycline response elements (TRE), which trigger the expression of Cre recombinase to mediate the recombination of loxP sequences targeted cells In this way, tamoxifen or 4-OHT drive the inducible Cre to the nucleus, where located at the reporter transgene [32,33] (Figure 3B). This system allows it promotes the recombination of loxP sequences, allowing the expression of the reporter us to perform lineage tracing at saturation [34], relying on the long-term administration (Figure 3A) The use of this particular system has been controversial, since high doses of of Dox and inducing reporter recombination in every single cell of a given lineage, overtamoxifen can delay mammary gland development [30]; the use of low doses coming the low recombination efficiency obtained by classic lineage tracing experiments (0.1 mg/g of mouse body weight) is a good balance between correct mammary epithelial using ER-dependent Cre lines. Some groups have used this technology to explore the capacity of different mammary epithelial cells to initiate tumors or metastasize, as well as to understand the potential mechanisms underlying cellular plasticity within breast tumors, which could lead to new therapeutic strategies for treating heterogeneous tumors in the near future
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