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Journal ArticleDOI

p130Cas alters the differentiation potential of mammary luminal progenitors by deregulating c-Kit activity.

TL;DR: High levels of p130Cas, via abnormal c‐Kit activation, promote mammary luminal cell plasticity, thus providing the conditions for the development of basal‐like breast cancer.
Abstract: It has recently been proposed that defective differentiation of mammary luminal progenitors predisposes to basal-like breast cancer. However, the molecular and cellular mechanisms involved are still unclear. Here, we describe that the adaptor protein p130Cas is a crucial regulator of mouse mammary epithelial cell (MMEC) differentiation. Using a transgenic mouse model, we show that forced p130Cas overexpression in the luminal progenitor cell compartment results in the expansion of luminal cells, which aberrantly display basal cell features and reduced differentiation in response to lactogenic stimuli. Interestingly, MMECs overexpressing p130Cas exhibit hyperactivation of the tyrosine kinase receptor c-Kit. In addition, we demonstrate that the constitutive c-Kit activation alone mimics p130Cas overexpression, whereas c-Kit downregulation is sufficient to re-establish proper differentiation of p130Cas overexpressing cells. Overall, our data indicate that high levels of p130Cas, via abnormal c-Kit activation, promote mammary luminal cell plasticity, thus providing the conditions for the development of basal-like breast cancer. Consistently, p130Cas is overexpressed in human triple-negative breast cancer, further suggesting that p130Cas upregulation may be a priming event for the onset of basal-like breast cancer.
Citations
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Journal ArticleDOI
TL;DR: Recent evidence that shows that inherent material properties may be engineered to dictate stem cell fate decisions are discussed, and a subset of the operative signal transduction mechanisms that have begun to emerge are overviewed.
Abstract: The stem cell/material interface is a complex, dynamic microenvironment in which the cell and the material cooperatively dictate one another's fate: the cell by remodelling its surroundings, and the material through its inherent properties (such as adhesivity, stiffness, nanostructure or degradability). Stem cells in contact with materials are able to sense their properties, integrate cues via signal propagation and ultimately translate parallel signalling information into cell fate decisions. However, discovering the mechanisms by which stem cells respond to inherent material characteristics is challenging because of the highly complex, multicomponent signalling milieu present in the stem cell environment. In this Review, we discuss recent evidence that shows that inherent material properties may be engineered to dictate stem cell fate decisions, and overview a subset of the operative signal transduction mechanisms that have begun to emerge. Further developments in stem cell engineering and mechanotransduction are poised to have substantial implications for stem cell biology and regenerative medicine.

787 citations

Journal ArticleDOI
TL;DR: Overall, the data show that a high level of KIT expression occurs infrequently in breast cancer, and KIT-positive breast cancers may not reflect "KIT up-regulation" because KIT is also expressed in normal breast epithelium.
Abstract: PURPOSE KIT (CD117) is a transmembrane tyrosine kinase representing a target for STI571 (Glivec) therapy. Some KIT-overexpressing solid tumors have responded favorably to STI571, potentially because of the presence of KIT-activating mutations. EXPERIMENTAL DESIGN To investigate the epidemiology of KIT overexpression and mutations, we investigated a series of 1654 breast cancers. All tumors were analyzed by immunohistochemistry in a tissue microarray format. RESULTS KIT expression was always present in normal breast epithelium. However, cancer analysis revealed the only 43 of 1654 (2.6%) tumors were KIT-positive. KIT expression was more frequent in medullary cancer (9 of 47 positive; 19.1%) than in any other histological tumor subtype (P < 0.001). KIT expression was significantly associated with high tumor grade (P < 0.0001) but unrelated to pT and pN categories or patient survival. Mutation analysis of exons 2, 8, 9, 11, 13, and 17 was negative in 10 KIT-positive tumors. CONCLUSIONS Overall, our data show that a high level of KIT expression occurs infrequently in breast cancer. KIT-positive breast cancers may not reflect \"KIT up-regulation\" because KIT is also expressed in normal breast epithelium. The lack of KIT mutations also argues against the therapeutic efficacy of STI571 in breast cancer.

65 citations

Journal ArticleDOI
TL;DR: An update on recently published studies describing signals regulating and regulated by CAS proteins, and evidence for biological activity of CAS proteins in normal development, cancer, and other pathological conditions is provided.
Abstract: The CAS family of scaffolding proteins has increasingly attracted scrutiny as important for regulation of cancer-associated signaling. BCAR1 (also known as p130Cas), NEDD9 (HEF1, Cas-L), EFS (Sin), and CASS4 (HEPL) are regulated by and mediate cell attachment, growth factor, and chemokine signaling. Altered expression and activity of CAS proteins are now known to promote metastasis and drug resistance in cancer, influence normal development, and contribute to the pathogenesis of heart and pulmonary disease. In this article, we provide an update on recently published studies describing signals regulating and regulated by CAS proteins, and evidence for biological activity of CAS proteins in normal development, cancer, and other pathological conditions.

44 citations


Cites background from "p130Cas alters the differentiation ..."

  • ...BCAR1 protein levels were elevated in 75% of analyzed tissue samples from the patients with triple negative breast cancer (44 out of 51) (70)....

    [...]

  • ...Mouse mammary epithelial cells (MMEC) with high levels of BCAR1 had increased activity of c-kit (70), and an interaction between BCAR1 and c-kit was found to be crucial for the proper differentiation of MMEC....

    [...]

Journal ArticleDOI
TL;DR: It is demonstrated LYN is a downstream effector of c-KIT in normal mammary cells and protective of apoptosis upon genotoxic stress and dual mechanisms—uncoupling from upstream signals and splice isoform ratios—drive the activity of LYN in aggressive breast cancers.

40 citations


Cites background from "p130Cas alters the differentiation ..."

  • ..., 2011), which is required for growth and survival of these cells (Regan et al., 2012; Tornillo et al., 2013) as well as the SRC family tyrosine kinase (SFK) LYN (Bach et al....

    [...]

01 Jan 2014
TL;DR: In this article, the authors provide an update on recently published studies describing signals regulating and regulated by scaffolding proteins, and evidence for biological activity of CAS proteins in normal development, cancer, and other pathological conditions.
Abstract: The CAS family of scaffolding proteins has increasingly attracted scrutiny as important for regulation of cancerassociated signaling. BCAR1 (also known as p130Cas), NEDD9 (HEF1, Cas-L), EFS (Sin), and CASS4 (HEPL) are regulated by and mediate cell attachment, growth factor, and chemokine signaling. Altered expression and activity of CAS proteins are now known to promote metastasis and drug resistance in cancer, influence normal development, and contribute to the pathogenesis of heart and pulmonary disease. In this article, we provide an update on recently published studies describing signals regulating and regulated by CAS proteins, and evidence for biological activity of CAS proteins in normal development, cancer, and other pathological conditions. V C 2014 IUBMB Life, 00(00):000‐000, 2014

36 citations

References
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Journal ArticleDOI
TL;DR: A panel of four antibodies (ER, HER1, HER2, and cytokeratin 5/6) can accurately identify basal-like tumors using standard available clinical tools and shows high specificity.
Abstract: Purpose: Expression profiling studies classified breast carcinomas into estrogen receptor (ER)+/luminal, normal breast-like, HER2 overexpressing, and basal-like groups, with the latter two associated with poor outcomes. Currently, there exist clinical assays that identify ER+/luminal and HER2-overexpressing tumors, and we sought to develop a clinical assay for breast basal-like tumors. Experimental Design: To identify an immunohistochemical profile for breast basal-like tumors, we collected a series of known basal-like tumors and tested them for protein patterns that are characteristic of this subtype. Next, we examined the significance of these protein patterns using tissue microarrays and evaluated the prognostic significance of these findings. Results: Using a panel of 21 basal-like tumors, which was determined using gene expression profiles, we saw that this subtype was typically immunohistochemically negative for estrogen receptor and HER2 but positive for basal cytokeratins, HER1, and/or c-KIT. Using breast carcinoma tissue microarrays representing 930 patients with 17.4-year mean follow-up, basal cytokeratin expression was associated with low disease-specific survival. HER1 expression was observed in 54% of cases positive for basal cytokeratins ( versus 11% of negative cases) and was associated with poor survival independent of nodal status and size. c-KIT expression was more common in basal-like tumors than in other breast cancers but did not influence prognosis. Conclusions: A panel of four antibodies (ER, HER1, HER2, and cytokeratin 5/6) can accurately identify basal-like tumors using standard available clinical tools and shows high specificity. These studies show that many basal-like tumors express HER1, which suggests candidate drugs for evaluation in these patients.

2,562 citations

Journal ArticleDOI
TL;DR: There are properties that define 'BRCAness' — that is, traits that some sporadic cancers share with those occurring in either BRCA1- or BRCa2-mutation carriers, which might have important implications for the clinical management of these cancers.
Abstract: Germline mutations in the BRCA1, BRCA2 and Fanconi anaemia genes confer cancer susceptibility, and the proteins encoded by these genes have distinct functions in related DNA-repair processes. Emerging evidence indicates that these processes are disrupted by numerous mechanisms in sporadic cancers. Collectively, there are properties that define 'BRCAness' — that is, traits that some sporadic cancers share with those occurring in either BRCA1- or BRCA2-mutation carriers. These common properties might have important implications for the clinical management of these cancers.

1,554 citations

Journal ArticleDOI
23 Feb 2006-Nature
TL;DR: The use of multi-parameter cell sorting and limiting dilution transplant analysis is reported to demonstrate the purification of a rare subset of adult mouse mammary cells that are able individually to regenerate an entire mammary gland within 6 weeks in vivo while simultaneously executing up to ten symmetrical self-renewal divisions.
Abstract: Elucidation of the cellular and molecular mechanisms that maintain mammary epithelial tissue integrity is of broad interest and paramount to the design of more effective treatments for breast cancer. Evidence from both in vitro and in vivo experiments suggests that mammary cell differentiation is a hierarchical process originating in an uncommitted stem cell with self-renewal potential. However, analysis of the properties and regulation of mammary stem cells has been limited by a lack of methods for their prospective isolation. Here we report the use of multi-parameter cell sorting and limiting dilution transplant analysis to demonstrate the purification of a rare subset of adult mouse mammary cells that are able individually to regenerate an entire mammary gland within 6 weeks in vivo while simultaneously executing up to ten symmetrical self-renewal divisions. These mammary stem cells are phenotypically distinct from and give rise to mammary epithelial progenitor cells that produce adherent colonies in vitro. The mammary stem cells are also a rapidly cycling population in the normal adult and have molecular features indicative of a basal position in the mammary epithelium.

1,550 citations

Journal ArticleDOI
20 Jan 2011-Nature
TL;DR: Evidence is also accumulating that cancers of distinct subtypes within an organ may derive from different 'cells of origin', and the identification of these crucial target cell populations may allow earlier detection of malignancies and better prediction of tumour behaviour.
Abstract: Both solid tumours and leukaemias show considerable histological and functional heterogeneity. It is widely accepted that genetic lesions have a major role in determining tumour phenotype, but evidence is also accumulating that cancers of distinct subtypes within an organ may derive from different 'cells of origin'. These cells acquire the first genetic hit or hits that culminate in the initiation of cancer. The identification of these crucial target cell populations may allow earlier detection of malignancies and better prediction of tumour behaviour, and ultimately may lead to preventive therapies for individuals at high risk of developing cancer.

1,346 citations

Journal ArticleDOI
TL;DR: It is found that breast tissue from BRCA1 mutation carriers harbors an expanded luminal progenitor population that shows factor-independent growth in vitro, and the findings suggest that an aberrant luminalprogenitor population is a target for transformation in BRCa1-associated basal tumors.
Abstract: Basal-like breast cancers arising in women carrying mutations in the BRCA1 gene, encoding the tumor suppressor protein BRCA1, are thought to develop from the mammary stem cell. To explore early cellular changes that occur in BRCA1 mutation carriers, we have prospectively isolated distinct epithelial subpopulations from normal mammary tissue and preneoplastic specimens from individuals heterozygous for a BRCA1 mutation. We describe three epithelial subsets including basal stem/progenitor, luminal progenitor and mature luminal cells. Unexpectedly, we found that breast tissue from BRCA1 mutation carriers harbors an expanded luminal progenitor population that shows factor-independent growth in vitro. Moreover, gene expression profiling revealed that breast tissue heterozygous for a BRCA1 mutation and basal breast tumors were more similar to normal luminal progenitor cells than any other subset, including the stem cell-enriched population. The c-KIT tyrosine kinase receptor (encoded by KIT) emerged as a key marker of luminal progenitor cells and was more highly expressed in BRCA1-associated preneoplastic tissue and tumors. Our findings suggest that an aberrant luminal progenitor population is a target for transformation in BRCA1-associated basal tumors .

1,339 citations

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