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Keratin 6A Marks Mammary Bipotential Progenitor Cells That Can Give Rise to a Unique Tumor Model Resembling Human Normal-Like Breast Cancer

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Keratin 6A Marks Mammary Bipotential Progenitor Cells That Can Give Rise to a Unique Tumor Model Resembling Human Normal-Like Breast Cancer Oncogene (2011) 30, 4399–4409 & 2011 Macmillan Publishers Limited All rights reserved 0950-9232/11 www.nature.com/onc ORIGINAL ARTICLE Keratin 6a marks mammary bipotential progenitor cells that can give rise to a unique tumor model resembling human normal-like breast cancer WBu1, J Chen2, GD Morrison1, S Huang3,4, CJ Creighton4, J Huang1, GC Chamness1, SG Hilsenbeck1,4, DR Roop2, AD Leavitt5 and Y Li1,2,3 1Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA; 2Dermatology and Charles C. Gates Regenerative Medicine and Stem Cell Biology Program, University of Colorado Denver, Aurora, CO, USA; 3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA; 4Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA and 5Department of Laboratory Medicine and Medicine, University of California, San Francisco, CA, USA Progenitor cells are considered an important cell of origin epigenetic changes. However, the breast epithelium is of human malignancies. However, there has not been any composed of cells at different stages of differentiation— single gene that can define mammary bipotential progeni- a small number of mammary stem cells and bipotential tor cells, and as such it has not been possible to use genetic progenitor cells give rise to larger populations of more methods to introduce oncogenic alterations into these cells differentiated ductal (or luminal) epithelial cells and in vivo to study tumorigenesis from them. Keratin 6a is myoepithelial (basal) cells (Shackleton et al., 2006; expressed in a subset of mammary luminal epithelial cells Stingl et al., 2006; Bai and Rohrschneider, 2010). These and body cells of terminal end buds. By generating differentiated progeny constitute the bulk of the transgenic mice using the Keratin 6a (K6a) gene promoter mammary epithelium. Stem and progenitor cells have to express tumor virus A (tva), which encodes the receptor been suggested to be the cells of origin for leukemia and for avian leukosis virus subgroup A (ALV/A), we provide solid cancers, including those arising in the colon, direct evidence that K6a þ cells are bipotential progenitor prostate and brain (Visvader, 2011). However, it has cells, and the first demonstration of a non-basal location been controversial whether breast cancers arise from for some biopotential progenitor cells. These K6a þ cells stem cells, progenitor cells or their differentiated were readily induced to form mammary tumors by progeny, or whether they may arise from different intraductal injection of RCAS (an ALV/A-derived vector) subsets of cells, in which case differences in the cell of carrying the gene encoding the polyoma middle T antigen. origin could be at least partly responsible for the Tumors in this K6a-tva line were papillary and resembled phenotypic heterogeneity of breast cancer (Li and the normal breast-like subtype of human breast cancer. Rosen, 2005; Lim et al., 2009; Molyneux et al., 2010). This is the first model of this subtype of human tumors and Mouse models can be very powerful in addressing thus may be useful for preclinical testing of targeted these issues. Many mouse models have been made to therapy for patients with normal-like breast cancer. These target oncogenic lesions primarily to the more differ- observations also provide direct in vivo evidence for the entiated luminal mammary cells through the use of the hypothesis that the cell of origin affects mammary tumor promoter of the gene encoding WAP (whey acidic phenotypes. protein) or the mouse mammary tumor virus (MMTV) Oncogene (2011) 30, 4399–4409; doi:10.1038/onc.2011.147; long terminal repeat (LTR), both of which are known to published online 2 May 2011 be more highly expressed in the bulk, more differen- tiated mammary epithelial cells (Vargo-Gogola and Keywords: Keratin 6; TVA; RCAS; PyMT; mammary Rosen, 2007). These studies have discovered that gland; normal-like breast cancer differentiated luminal cells may be the origin of ErbB2 þ breast cancer (Li et al., 2003; Andrechek et al., 2004; Henry et al., 2004; Jeselsohn et al., 2010). However, it has not been possible to introduce genetic alterations Introduction selectively into the precursor populations of mammary cells in vivo to investigate their tumor susceptibility or Human breast cancers are heterogeneous in several their influence on the phenotypes of the resulting aspects, including histopathological features and gene tumors. This was largely a technical issue: To manip- expression profiles. These tumors arise from the breast ulate cancer genes for in vivo tumor studies, a single gene epithelium as a result of genetic mutations and promoter typically has to be used to direct the transgenic expression of an oncogene (or Cre for Correspondence: Dr Y Li, Breast Center, Baylor College of Medicine, deletion of a tumor-suppressor gene). s-SHIP, axin2 1 Baylor Plaza, BCM 600, Houston, TX 77030, USA. E-mail: [email protected] and low-density lipoprotein receptor-related protein 5 Received 24 March 2010; revised 16 March 2011; accepted 23 March (LRP5) have recently been reported to enrich for 2011; published online 2 May 2011 mammary stem cells (Badders et al., 2009; Bai and Mouse model of normal-like breast cancer WBuet al 4400 Rohrschneider, 2010; Zeng and Nusse, 2010), whereas plementary Figure 2). To confirm that TVA þ cells also CD24 and Sca1 could classify mammary cells into express K6a, mammary sections from three of the different differentiation subsets based on levels of their estrogen/progesterone-treated 7-week-old K6a-tva mice expression (Welm et al., 2002; Sleeman et al., 2006); but were co-stained for TVA and pan-K6. All TVA þ cells none could define mammary progenitor cells. were also stained for K6, confirming that tva expression The keratin 6 (K6 or Krt6) gene family is composed of is restricted to K6 þ cells, although only a subset three members, namely K6a, K6b and K6hf (or Krt75) (26±4%) of K6 þ cells was also positive for TVA (Wojcik et al., 2001). Only K6a isexpressedinthe (Figures 1e and f). To further verify that the tva mammary gland, and only in a very small fraction of expression is restricted to the K6 þ cell population, we mammary luminal epithelial cells based on co-staining also stained sections of hyperplastic mammary glands withkeratin8andestrogenreceptor(Smithet al., 1990; Li from three 12-week-old K6a-tva/MMTV-Wnt1 bi-trans- et al., 2003; Grimm et al., 2006). K6a is found in more genic mice and sections of mammary tumors arising in mammary cells when the ductal tree expands, such as at this line of mice. Again, all TVA þ cells were also the onset of puberty or early pregnancy (Smith et al., 1990; positive for K6, whereas 65±9% and 22±5% of K6 þ Grimm et al., 2006). This distribution pattern is consistent cells in these hyperplastic and cancerous mammary with the distribution of mammary progenitors. Further- tissues, respectively, also stained for TVA (Supplemen- more, K6a has been found by quantitative PCR to be more tary Figures 3a and b). In addition, we detected TVA in highly expressed in the population of mammary cells that K6 þ populations of cells in a number of non-mammary are enriched for cells with colony-forming potential in tissues, including the skin (in the outer root sheath of the collagen gel (Stingl et al., 2006), but it has not been shown hair follicle), esophagus, trachea, papilla of the dorsal what percentage of cells in this population express K6a, tongue and sole of the foot (Supplementary Figure 3c), and whether K6a þ cells in this population can actually but not aberrantly in K6-negative tissues, including the form a colony or have other progenitor properties. Here, connective muscle and nervous tissues (data not shown). wereportthatK6aþ cells in the mammary gland are As expected of K6, after topical treatment with phorbol indeed bipotential progenitor cells and that they can be ester 12-O-tetradecanoylphorbol-13 acetate, TVA was induced to form mammary tumors that resemble the also induced in the epidermis in the skin, ear and foot, normal-like breast cancer subtype in patients. and it continued to be restricted to the K6 þ cell population (Supplementary Figure 3c and data not shown). Collectively, these data demonstrate that tva Results expression is restricted to the K6 þ subset of cells in this K6a-tva transgenic line. The lack of detectable TVA in Generation of K6a-tva BAC transgenic mice some of the K6 þ cells in these tissues may be because of To conclusively determine whether K6a þ cells are lower TVA detection sensitivity relative to that for K6, progenitor cells, it was necessary to isolate live K6a þ shorter TVA half-life or the loss of transcriptional cells away from the bulk of the mammary epithelium regulatory elements in this BAC construct. and test them in commonly used progenitor cell assays, The expression of tva was also expected to cause these such as colony-forming and transplantation assays. K6a K6a þ cells to be susceptible to infection by ALV/A (Du is a cytoskeleton protein rather than a surface protein; et al., 2006), a useful feature for virus-mediated lineage hence, it was not amenable to antibody-mediated tracing and introduction of oncogenes for tumor fluorescence-activated cell sorting (FACS) of live cells. induction. To confirm that the TVA produced in K6a- To isolate live K6a þ cells, we placed tumor virus A tva mice was capable of mediating infection by RCAS (tva)—a gene encoding the cell-surface receptor for an (a modified version of ALV/A), we injected RCAS-GFP avian leukosis virus, subgroup A (ALV/A) (Bates et al., (green fluorescent protein) intraductally into mammary 1993)—behind the K6a promoter in a BAC transgenic glands in nine K6a-tva mice at 5 weeks of age (107 IU per construct (Supplementary Figure 1).
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