From milk to malignancy: the role of mammary stem cells in development, pregnancy and breast cancer

Tiede, Benjamin; Kang, Yibin

doi:10.1038/cr.2011.11

Cited by 87 publications

(81 citation statements)

References 102 publications

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“…The normal breast in young women is enriched with immature mammary cell subpopulations (stem cells and progenitors), which have been shown to increase significantly with pregnancy, menstrual cycles, and lactation. RANKL has been shown to be a key mediator of this effect and RANKL inhibition could be antiproliferative as well as mediate reductions in the mammary stem cell compartment which is thought to predispose to cancer (41)(42)(43). Similarly, Lim and colleagues recently proposed that the cell of origin of BRCA1-associated and "basal-like" tumors were probably luminal progenitor cells rather than the stem-cell enriched population with c-kit identified as a key marker (44).…”

Section: /Her2mentioning

confidence: 99%

Elucidating Prognosis and Biology of Breast Cancer Arising in Young Women Using Gene Expression Profiling

Azim

Michiels

Bedard

et al. 2012

Clinical Cancer Research

312

227

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Purpose: Breast cancer in young women is associated with poor prognosis. We aimed to define the role of gene expression signatures in predicting prognosis in young women and to understand biological differences according to age.Experimental Design: Patients were assigned to molecular subtypes [estrogen receptor (ER)À )] using a three-gene classifier. We evaluated whether previously published proliferation, stroma, and immune-related gene signatures added prognostic information to Adjuvant! online and tested their interaction with age in a Cox model for relapse-free survival (RFS). Furthermore, we evaluated the association between candidate age-related genes or gene sets with age in an adjusted linear regression model. Results: A total of 3,522 patients (20 data sets) were eligible. Patients aged 40 years or less had a higher proportion of ER À /HER2 À tumors (P < 0.0001) and were associated with poorer RFS after adjustment for breast cancer subtype, tumor size, nodal status, and histologic grade and stratification for data set and treatment modality (HR ¼ 1.34, 95% CI ¼ 1.10-1.63, P ¼ 0.004). The proliferation gene signatures showed no significant interaction with age in ER þ /HER2 À tumors after adjustment for Adjuvant! online. Further analyses suggested that breast cancer in the young is enriched with processes related to immature mammary epithelial cells (luminal progenitors, mammary stem, c-kit, RANKL) and growth factor signaling in two independent cohorts (n ¼ 1,188 and 2,334). Conclusions: Proliferation-related prognostic gene signatures can aid treatment decision-making for young women. However, breast cancer arising at a young age seems to be biologically distinct beyond subtype distribution. Separate therapeutic approaches such as targeting RANKL or mammary stem cells could therefore be needed.

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Section: /Her2mentioning

confidence: 99%

Elucidating Prognosis and Biology of Breast Cancer Arising in Young Women Using Gene Expression Profiling

Azim

Michiels

Bedard

et al. 2012

Clinical Cancer Research

312

227

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“…Moreover, both in humans and mice pregnancy strongly influences mammary tumorigenesis. 25,26 During pregnancy, p63 is also expressed in the basal cell layer, 20 again with DNp63 predominating. 27 Moreover, Ihh signaling is enhanced and likely contributes to the expansion of DNp63 negative progenitors to allow mammary gland 'elaboration'.…”

mentioning

confidence: 99%

p63 is a prosurvival factor in the adult mammary gland during post-lactational involution, affecting PI-MECs and ErbB2 tumorigenesis

et al. 2014

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In embryogenesis, p63 is essential to develop mammary glands. In the adult mammary gland, p63 is highly expressed in the basal cell layer that comprises myoepithelial and interspersed stem/progenitor cells, and has limited expression in luminal epithelial cells. In adult skin, p63 has a crucial role in the maintenance of epithelial stem cells. However, it is unclear whether p63 also has an equivalent role as a stem/progenitor cell factor in adult mammary epithelium. We show that p63 is essential in vivo for the survival and maintenance of parity-identified mammary epithelial cells (PI-MECs), a pregnancy-induced heterogeneous population that survives post-lactational involution and contain multipotent progenitors that give rise to alveoli and ducts in subsequent pregnancies. p63 þ / À glands are normal in virgin, pregnant and lactating states. Importantly, however, during the apoptotic phase of post-lactational involution p63 þ / À glands show a threefold increase in epithelial cell death, concomitant with increased activation of the oncostatin M/Stat3 and p53 pro-apoptotic pathways, which are responsible for this phase. Thus, p63 is a physiologic antagonist of these pathways specifically in this regressive stage. After the restructuring phase when involution is complete, mammary glands of p63 þ / À mice again exhibit normal epithelial architecture by conventional histology. However, using Rosa LSL-LacZ ;WAP-Cre transgenics (LSL-LacZ, lox-stop-lox b-galactosidase), a genetic in vivo labeling system for PI-MECs, we find that p63 þ / À glands have a 30% reduction in the number of PI-MEC progenitors and their derivatives. Importantly, PI-MECs are also cellular targets of pregnancy-promoted ErbB2 tumorigenesis. Consistent with their PI-MEC pool reduction, one-time pregnant p63 þ / À ErbB2 mice are partially protected from breast tumorigenesis, exhibiting extended tumor-free and overall survival, and reduced tumor multiplicity compared with their p63 þ / þ ErbB2 littermates. Conversely, in virgin ErbB2 mice p63 heterozygosity provides no survival advantage. In sum, our data establish that p63 is an important survival factor for pregnancy-identified PI-MEC progenitors in breast tissue in vivo.

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“…A major limitation of both the morphological and the label retention methods is that they do not allow easy isolation of large numbers of pure MaSC populations for use in in vitro or in vivo assays [90]. With respect to the human mammary gland, identification of authentic MaSCs is considered a greater challenge due to the difficulty in obtaining normal tissue samples and the lack of an ideal in vitro reconstitution system.…”

Section: Mammary Gland Stem Cells (Mascs)mentioning

confidence: 99%

Adult Gland Derived Stem Cells (Gdscs); Potentials, Hurdles and Expectations

M¹

2014

J Stem Cell Res Ther

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From milk to malignancy: the role of mammary stem cells in development, pregnancy and breast cancer

Cited by 87 publications

References 102 publications

Elucidating Prognosis and Biology of Breast Cancer Arising in Young Women Using Gene Expression Profiling

Elucidating Prognosis and Biology of Breast Cancer Arising in Young Women Using Gene Expression Profiling

p63 is a prosurvival factor in the adult mammary gland during post-lactational involution, affecting PI-MECs and ErbB2 tumorigenesis

Adult Gland Derived Stem Cells (Gdscs); Potentials, Hurdles and Expectations

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