β1 Integrin deletion from the basal compartment of the mammary epithelium affects stem cells

Taddei, Ilaria; Deugnier, Marie‐Ange; Faraldo, Marisa M.; Petit, Valérie; Bouvard, Daniel; Medina, Daniel; Fässler, Reinhard; Thiery, Jean Paul; Glukhova, Marina A.

doi:10.1038/ncb1734

Cited by 225 publications

(255 citation statements)

References 27 publications

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“…Such cells have been suggested as the origin of ER-positive breast cancer (Dontu et al, 2003;Molyneux et al, 2007;Arendt et al, 2011), but until now it has not proven possible to prospectively isolate them. Importantly, cKit was required for progenitor function and is therefore only the second mammary stem/progenitor marker, after b1 integrin (Taddei et al, 2008), to be shown to have a functional role in the gland. Luminal Sca-1 À ER À c-Kit þ cells formed >50% of the epithelial content of the mammary gland, consistent with a report showing reciprocal staining of c-KIT and ER in the human breast (Westbury et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Terminally differentiated cells do not transplant or form colonies in vitro Stingl et al, 2006;AsselinLabat et al, 2007;Sleeman et al, 2007). Using flow cytometry and functional assays, stem cells have been localised to the basal cell layer, whereas progenitors are found in large numbers in the luminal population Stingl et al, 2006;AsselinLabat et al, 2007;Sleeman et al, 2007;Taddei et al, 2008). We have recently demonstrated that oestrogen receptor-alpha-negative (ER À ) luminal progenitors are the origin of BRCA1-associated breast cancers and likely of the majority of 'basal-like' breast cancers not linked to a family history (Molyneux et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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c-Kit is required for growth and survival of the cells of origin of Brca1-mutation-associated breast cancer

et al. 2011

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BRCA1 mutation-associated breast cancer originates in oestrogen receptor-alpha-negative (ER À ) progenitors in the mammary luminal epithelium. These cells also express high levels of the Kit gene and a recent study demonstrated a correlation between Brca1 loss and Kit over-expression in the mammary epithelium. However, the functional significance of c-Kit expression in the mammary gland is unknown. To address this, c-Kit À and c-Kit þ mammary epithelial subsets were isolated by flow cytometry, characterised for expression of lineage-specific cell markers and functionally analysed by in vitro colony forming and in vivo transplantation assays. The results confirm that the majority of luminal ER À progenitors are c-Kit þ , but also that most stem cells and the differentiated cell populations are c-Kit À . A subset of c-Kit þ cells with high proliferative potential was found in the luminal ER þ population, however, suggesting the existence of a distinct luminal ER þ progenitor cell type. Analysis of mouse Brca1 mammary tumours demonstrated that they expressed Kit and its downstream effector Lyn at levels comparable to the most strongly c-Kit þ luminal ER À progenitors. Consistent with c-Kit being a progenitor cell marker, in vitro threedimensional differentiation of c-Kit þ cells resulted in a loss of c-Kit expression, whereas c-Kit over-expression prevented normal differentiation in vivo. Furthermore, c-Kit was a functional marker of proliferative potential, as c-Kit inhibition by short hairpin knockdown prevented normal epithelial growth and caused cells to undergo apoptosis. Therefore, c-Kit defines distinct progenitor populations in the mammary epithelium and is critical for mammary progenitor survival and proliferation. Importantly, c-Kit is only the second mammary epithelial stem/progenitor marker to be shown to have a functional role in the mammary epithelium and the first marker to be shown to be required for progenitor cell function. The c-Kit signalling network has potential as a target for therapy and/or prevention in BRCA1-associated breast cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

c-Kit is required for growth and survival of the cells of origin of Brca1-mutation-associated breast cancer

et al. 2011

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“…A luciferase-based transgenic mouse model for MaSC activity did reveal luciferaseexpressing cells in both basal and myoepithelial locations [22]. Notably, when the MaSC marker CD29 is deleted from the basal compartment of the mammary gland, the mammary epithelial cells can no longer reconstitute a new mammary gland, but they can form alveoli late in pregnancy [18], suggesting a distinct MaSC population. Similar results were also obtained when the Wnt receptor LPR5 was deleted [23].…”

Section: Identification Of Mascsmentioning

confidence: 99%

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

Tiede

Kang

2011

Cell Res

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Adult stem cells of the mammary gland (MaSCs) are a highly dynamic population of cells that are responsible for the generation of the gland during puberty and its expansion during pregnancy. In recent years significant advances have been made in understanding how these cells are regulated during these developmentally important processes both in humans and in mice. Understanding how MaSCs are regulated is becoming a particularly important area of research, given that they may be particularly susceptible targets for transformation in breast cancer. Here, we summarize the identification of MaSCs, how they are regulated and the evidence for their serving as the origins of breast cancer. In particular, we focus on how changes in MaSC populations may explain both the increased risk of developing aggressive ER/PR(−) breast cancer shortly after pregnancy and the long-term decreased risk of developing ER/ PR(+) tumors.

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“…Fragments of mammary epithelium or 1,000-5,000 sorted BCs in 10 ll of 50% growth-factor-reduced matrigel (BD Biosciences, San Diego, CA, http://www.bdbiosciences.com) were implanted into the inguinal fat pads of 3-week-old nude BALB/c females cleared of endogenous epithelium as described elsewhere [23]. In limiting dilution assays, 500-100,000 of total unsorted mammary cells per fat pad were transplanted in matrigel.…”

Section: Transplantation Assaysmentioning

confidence: 99%

“…The inguinal mammary glands of four to six 20-week-old virgin females were pooled to prepare single-cell suspensions, and cells were processed for flow cytometry as described [12,13,23]. The following conjugated antibodies were used: anti-CD24-PE (clone M1/69; BD Pharmingen, San Diego, CA, http:// www.bdbiosciences.com), anti-CD49f-FITC (clone GoH3; BD Pharmingen), anti-CD45-APC (clone 30-F11; Biolegend, San Diego, CA, http://www.biolegend.com), anti-CD31-APC (clone MEC13.3; Biolegend), and anti-Ly6A/E-PE-Cy5 (clone D7; eBiosciences, San Diego, CA, http://www.ebiosciences.com).…”

Section: Preparation Of Mammary Epithelial Cells and Cell Cycle Analysismentioning

confidence: 99%

The Proto-Oncogene Myc Is Essential for Mammary Stem Cell Function

et al. 2012

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The mammary epithelium comprises two major cell lineages: basal and luminal. Basal cells (BCs) isolated from the mammary epithelium and transplanted into the mouse mammary fat pad cleared from the endogenous epithelium regenerate the mammary gland, strongly suggesting that the basal epithelial compartment harbors a long-lived cell population with multipotent stem cell potential. The luminal cell layer is devoid of the regenerative potential, but it contains cells with clonogenic capacity, the luminal progenitors. Mammary BCs and luminal progenitors express high levels of the transcription factor Myc. Here, we show that deletion of Myc from mammary basal epithelial cells led to impaired stem cell self-renewal as evaluated by limiting dilution and serial transplantation assays. Luminal progenitor population was significantly diminished in mutant epithelium suggesting control by the BC layer. Colony formation assay performed with isolated BCs showed that clonogenic capacity was abolished by Myc deletion. Moreover, transplanted BCs depleted of Myc failed to produce epithelial outgrowths. Stimulation with ovarian hormones estrogen (E) and progesterone (P) partially rescued the repopulation capacity of Myc-depleted BCs; however, the Myc-deficient mammary epithelium developed in response to E/P treatment lacked stem and progenitor cells. This study provides the first evidence that in the mammary gland, Myc has an essential nonredundant function in the maintenance of the self-renewing multipotent stem cell population responsible for the regenerative capacity of the mammary epithelium and is required downstream from ovarian hormones, for the control of mammary stem and progenitor cell functions.

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β1 Integrin deletion from the basal compartment of the mammary epithelium affects stem cells

Cited by 225 publications

References 27 publications

c-Kit is required for growth and survival of the cells of origin of Brca1-mutation-associated breast cancer

c-Kit is required for growth and survival of the cells of origin of Brca1-mutation-associated breast cancer

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

The Proto-Oncogene Myc Is Essential for Mammary Stem Cell Function

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