BRCA1 Basal-like Breast Cancers Originate from Luminal Epithelial Progenitors and Not from Basal Stem Cells

Molyneux, Gemma; Geyer, Felipe C.; Magnay, Fiona-Ann; McCarthy, Afshan; Kendrick, Howard; Natrajan, Rachael; Mackay, Alan; Grigoriadis, Anita; Tutt, Andrew; Ashworth, Alan; Reis‐Filho, Jorge S.; Smalley, Matthew J.

doi:10.1016/j.stem.2010.07.010

Cited by 662 publications

(735 citation statements)

References 48 publications

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“…Within the basal population, a CD24 þ /Low Sca-1 À CD49f Low population (previously identified as mainly myoepithelial cells) and a CD24 þ /Low Sca-1 À CD49f High population (previously shown to be highly enriched for mammary stem cells) could be recognised Sleeman et al, 2007). Within the luminal population, CD24 þ /High Sca-1 À luminal cells (mainly ER À progenitors) and CD24 þ /High Sca-1 þ luminal cells (mainly differentiated ER þ cells) could be distinguished ( Figure 1a and Supplementary Figure 1) (Sleeman et al, 2007;Molyneux et al, 2010).…”

Section: Resultsmentioning

confidence: 81%

“…Using functional assays, we show that c-Kit expression marks progenitors with high in vitro proliferative potential, but that the majority of mammary stem cells (MaSCs) are c-Kit À . We demonstrate that in a mouse model of Brca1 breast cancer that phenocopies the human disease (Molyneux et al, 2010), the tumours express Kit and its downstream effector Lyn at levels comparable to those luminal ER À progenitors, which are most strongly c-Kit þ . Importantly, we demonstrate that c-Kit is required for mammary epithelial cell survival.…”

Section: Introductionmentioning

confidence: 88%

“…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). Understanding the molecular regulation of these cells in particular is therefore important for identifying novel approaches to breast cancer prevention and therapy.…”

Section: Introductionmentioning

confidence: 99%

“…The identification and molecular characterisation of stem, progenitor and differentiated cell hierarchies in complex tissues is key to understanding not only normal cellular homoeostasis but also the origins of cancer (Molyneux et al, 2010). Identifying the key biological processes common to tumours and the cells from which they develop will help define the pathways/networks required for tumour initiation and maintenance.…”

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: Resultsmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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“…5,14 This has been emphasized in a recent study, which suggested that at least a subgroup of basal-like breast cancers may originate from luminal progenitors rather than basal/ myoepithelial cells of the breast, 57 and confirmed by the results of conditional mouse models. 58 In this context, it is important to note that histogenesis and differentiation are two distinct processes although often mistakenly used as synonyms. Basal-like and triple-negative breast cancers…”

Section: What Is a Basal-like Breast Cancer?mentioning

confidence: 99%

Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists

et al. 2011

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Breast cancer is a heterogeneous disease encompassing a variety of entities with distinct morphological features and clinical behaviors. Although morphology is often associated with the pattern of molecular aberrations in breast cancers, it is also clear that tumors of the same histological type show remarkably different clinical behavior. This is particularly true for 'basal-like cancer', which is an entity defined using gene expression analysis. The purpose of this article was to review the current state of knowledge of basal-like breast cancers, to discuss the relationship between basal-like and triple-negative breast cancers, and to clarify practical implications of these diagnoses for pathologists and oncologists.

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Postpartum Breast Cancer and Survival in Women With Germline BRCA Pathogenic Variants

Zhang,

Ye,

Bernhardt

et al. 2024

JAMA Netw Open

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ImportanceIn young-onset breast cancer (YOBC), a diagnosis within 5 to 10 years of childbirth is associated with increased mortality. Women with germline BRCA1/2 pathogenic variants (PVs) are more likely to be diagnosed with BC at younger ages, but the impact of childbirth on mortality is unknown.ObjectiveTo determine whether time between most recent childbirth and BC diagnosis is associated with mortality among patients with YOBC and germline BRCA1/2 PVs.Design, Setting, and ParticipantsThis prospective cohort study included women with germline BRCA1/2 PVs diagnosed with stage I to III BC at age 45 years or younger between 1950 and 2021 in the United Kingdom, who were followed up until November 2021. Data were analyzed from December 3, 2021, to November 29, 2023.ExposureTime between most recent childbirth and subsequent BC diagnosis, with recent childbirth defined as 0 to less than 10 years, further delineated to 0 to less than 5 years and 5 to less than 10 years.Main Outcomes and MeasuresThe primary outcome was all-cause mortality, censored at 20 years after YOBC diagnosis. Mortality of nulliparous women was compared with the recent post partum groups and the 10 or more years post partum group. Cox proportional hazards regression analyses were adjusted for age, tumor stage, and further stratified by tumor estrogen receptor (ER) and BRCA gene status.ResultsAmong 903 women with BRCA PVs (mean [SD] age at diagnosis, 34.7 [6.1] years; mean [SD] follow-up, 10.8 [9.8] years), 419 received a BC diagnosis 0 to less than 10 years after childbirth, including 228 women diagnosed less than 5 years after childbirth and 191 women diagnosed 5 to less than 10 years after childbirth. Increased all-cause mortality was observed in women diagnosed within 5 to less than 10 years post partum (hazard ratio [HR], 1.56 [95% CI, 1.05-2.30]) compared with nulliparous women and women diagnosed 10 or more years after childbirth, suggesting a transient duration of postpartum risk. Risk of mortality was greater for women with ER-positive BC in the less than 5 years post partum group (HR, 2.35 [95% CI, 1.02-5.42]) and ER-negative BC in the 5 to less than 10 years post partum group (HR, 3.12 [95% CI, 1.22-7.97]) compared with the nulliparous group. Delineated by BRCA1 or BRCA2, mortality in the 5 to less than 10 years post partum group was significantly increased, but only for BRCA1 carriers (HR, 2.03 [95% CI, 1.15-3.58]).Conclusions and RelevanceThese findings suggest that YOBC with germline BRCA PVs was associated with increased risk for all-cause mortality if diagnosed within 10 years after last childbirth, with risk highest for ER-positive BC diagnosed less than 5 years post partum, and for ER-negative BC diagnosed 5 to less than 10 years post partum. BRCA1 carriers were at highest risk for poor prognosis when diagnosed at 5 to less than 10 years post partum. No such associations were observed for BRCA2 carriers. These results should inform genetic counseling, prevention, and treatment strategies for BRCA PV carriers.

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BRCA1 Basal-like Breast Cancers Originate from Luminal Epithelial Progenitors and Not from Basal Stem Cells

Cited by 662 publications

References 48 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

Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists

Postpartum Breast Cancer and Survival in Women With Germline BRCA Pathogenic Variants

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