Rare steroid receptor-negative basal-like tumorigenic cells in luminal subtype human breast cancer xenografts

Horwitz, Kathryn B.; Dye, Wendy W.; Harrell, J. Chuck; Kabos, Peter; Sartorius, Carol A.

doi:10.1073/pnas.0706216105

Cited by 125 publications

(149 citation statements)

References 31 publications

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“…The presence of P was required for the expansion of basal/myoepithelial tumor cells that frequently expressed PRB similar to normal rat basal/ myoepithelial cells [19]. The expansion of basal/ myoepithelial cells in tumors from rats treated with E+P is consistent with previous findings that PS treatment leads to an expansion of rare K5+ T47D breast cancer cells in vitro [27]. Moreover, it has been shown that, when combined with E, both PS and P result in accumulation of basal/myoepithelial cells in xenografts of T47D cells in immunodeficient mice [28].…”

Section: Discussionsupporting

confidence: 80%

Progesterone Decreases Levels of the Adhesion Protein E-Cadherin and Promotes Invasiveness of Steroid Receptor Positive Breast Cancers

et al. 2013

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Progestins are reported to increase the risk of invasive breast cancers in postmenopausal women receiving hormone therapy with estrogen plus progestin. We report here that estrogen and progesterone receptor positive (ER+PR+) rat mammary tumors arising in the presence of estrogen and progesterone exhibit increased invasiveness and decreased expression of E-cadherin protein compared with tumors growing in the presence of estrogen alone. A similar decrease of Ecadherin expression was observed in human ER+PR+ invasive ductal carcinoma compared with ductal carcinoma in situ. In agreement with findings in the rat, estrogen plus progestin R5020 treatment decreased E-cadherin expression in vitro in T47D human breast cancer cells. Decrease of E-cadherin protein was mediated by progesterone receptor B (PRB) and dependent on the activation of the Wnt pathway. These results suggest that progesterone signaling via PRB contributes to tumor invasiveness and can provide an important therapeutic target for treatment of invasive ER+PR+ breast cancers.

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Section: Discussionsupporting

confidence: 80%

Progesterone Decreases Levels of the Adhesion Protein E-Cadherin and Promotes Invasiveness of Steroid Receptor Positive Breast Cancers

et al. 2013

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“…Our failure to identify CSC markers in luminal breast tumors shows that the tumorsphere assay is not appropriate for the identification of luminal CSC, and that other strategies must be pursued. A recent study has identified a potential hormone-independent CSC population (ER À PR À CK5 þ CD44 þ ) in a luminal cell line, raising the possibility that CSCs may drive endocrine resistance in hormone-dependent breast cancers [31]. Moreover, recent data also suggest that the residual breast tumor cell populations surviving after hormone therapy may be enriched in populations of cells with both tumor-initiating and mesenchymal features [32,33].…”

Section: Discussionmentioning

confidence: 96%

Mevalonate Metabolism Regulates Basal Breast Cancer Stem Cells and Is a Potential Therapeutic Target

et al. 2012

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There is increasing evidence that breast tumors are organized in a hierarchy, with a subpopulation of tumorigenic cancer cells, the cancer stem cells (CSCs), which sustain tumor growth. The characterization of protein networks that govern CSC behavior is paramount to design new therapeutic strategies targeting this subpopulation of cells. We have sought to identify specific molecular pathways of CSCs isolated from 13 different breast cancer cell lines of luminal or basal/mesenchymal subtypes. We compared the gene expression profiling of cancer cells grown in adherent conditions to those of matched tumorsphere cultures. No specific pathway was identified to be commonly regulated in luminal tumorspheres, resulting from a minor CSC enrichment in tumorsphere passages from luminal cell lines. However, in basal/mesenchymal tumorspheres, the enzymes of the mevalonate metabolic pathway were overexpressed compared to those in cognate adherent cells. Inhibition of this pathway with hydroxy-3-methylglutaryl CoA reductase blockers resulted in a reduction of breast CSC independent of inhibition of cholesterol biosynthesis and of protein farnesylation. Further modulation of this metabolic pathway demonstrated that protein geranylgeranylation (GG) is critical to breast CSC maintenance. A small molecule inhibitor of the geranylgeranyl transferase I (GGTI) enzyme reduced the breast CSC subpopulation both in vitro and in primary breast cancer xenografts. We found that the GGTI effect on the CSC subpopulation is mediated by inactivation of Ras homolog family member A (RHOA) and increased accumulation of P27 kip1 in the nucleus. The identification of protein GG as a major contributor to CSC maintenance opens promising perspectives for CSC targeted therapy in basal breast cancer. STEM

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“…These CSCs were detected by their ability to generate heterogeneous tumours when transplanted into primary and secondary recipient immune-compromised mice. Several follow-up papers have also demonstrated that some human breast cancer cell lines have a CSC component that shares this phenotype [75][76][77][78]. However, it appears that the EpCAM + CD44 + CD24 −/low phenotype is not a universal breast CSC profile, since a recent report has demonstrated that mammospheres could be generated from a pleural effusion that did not contain any CD44…”

Section: Stem Cells Progenitor Cells and Cancermentioning

confidence: 99%

Detection and analysis of mammary gland stem cells

Stingl

2008

The Journal of Pathology

141

154

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Emerging evidence from a variety of tissue types, including the mammary gland, suggests that normal stem and progenitor cells are the likely targets for malignant transformation, and that these transformed cells can function as cancer stem cells that drive tumour growth. In order to develop therapies that target these cancer stem cells, it is essential to determine the molecular mechanisms that regulate the growth and differentiation of these cells and their normal counterparts. To this end, a number of quantitative robust clonal assays have been developed that can detect the presence of human and mouse mammary stem and progenitor cells. These assays, when used in conjunction with cell-sorting strategies, have permitted the prospective isolation and characterization of a variety of cell types, including stem cells. Evidence to date indicates that these stem cells exhibit properties of basal mammary cells, possess extensive self-renewal properties, and are capable of generating a large number of phenotypically-distinct progenitor cells, many of which display characteristics of luminal cells. This review article will focus on the assays used to detect mammary stem and progenitor cells, some of the properties of these cells and their progeny and how they relate to the cancer stem cells that drive breast tumour growth.

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Rare steroid receptor-negative basal-like tumorigenic cells in luminal subtype human breast cancer xenografts

Cited by 125 publications

References 31 publications

Progesterone Decreases Levels of the Adhesion Protein E-Cadherin and Promotes Invasiveness of Steroid Receptor Positive Breast Cancers

Progesterone Decreases Levels of the Adhesion Protein E-Cadherin and Promotes Invasiveness of Steroid Receptor Positive Breast Cancers

Mevalonate Metabolism Regulates Basal Breast Cancer Stem Cells and Is a Potential Therapeutic Target

Detection and analysis of mammary gland stem cells

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