Characterization of epithelial phenotypes in mortal and immortal human breast cells

Paine, Terry Maloney; Soule, Herbert D.; Pauley, Robert J.; Dawson, Peter J.

doi:10.1002/ijc.2910500323

Cited by 90 publications

(70 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…MCF-12A cells were a generous gift of Prof. H. Phillip Koeffler (Cedars-Sinai Medical Ctr/University of California at Los Angeles School of Medicine, Los Angeles, CA). These cells are a nontumorigenic epithelial cell line established from tissue taken at reduction mammoplasty from a nulliparous patient with fibrocystic breast disease that contained focal areas of intraductal hyperplasia (32). They are not tumorigenic in immunosuppressed mice but do form colonies in semisolid medium.…”

Section: Methodsmentioning

confidence: 99%

Altered Nuclear Receptor Corepressor Expression Attenuates Vitamin D Receptor Signaling in Breast Cancer Cells

Banwell¹,

MacCartney²,

Guy

et al. 2006

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose:We hypothesized that deregulated corepressor actions, with associated histone deacetylation activity, epigenetically suppressed vitamin D receptor (VDR) responsiveness and drives resistance towards 1a,25-dihydroxyvitamin D 3 . Experimental Design: Profiling, transcriptional, and proliferation assays were undertaken in 1a,25(OH) 2 D 3 -sensitive MCF-12A nonmalignant breast epithelial cells, a panel of breast cancer cell lines, and a cohort of primary breast cancer tumors (n = 21). Results: Elevated NCoR1 mRNA levels correlated with suppressed regulation of VDR target genes and the ability of cells to undergo arrest in G 1 of the cell cycle. A similar increased ratio of corepressor mRNA to VDR occurred in matched primary tumor and normal cells, noticeably in estrogen receptor a^negative (n = 7) tumors. 1a,25(OH) 2 D 3 resistance in cancer cell lines was targeted by cotreatments with either 1a,25(OH) 2 D 3 or a metabolically stable analogue (RO-26-2198) in combination with either trichostatin A (TSA; histone deacetylation inhibitor) or 5-aza-2V-deoxycytidine (DNA methyltransferase inhibitor). Combinations of vitamin D 3 compounds with TSA restored VDR antiproliferative signaling (target gene regulation, cell cycle arrest, and antiproliferative effects in liquid culture) to levels which were indistinguishable from MCF-12A cells. Conclusions: Increased NCoR1 mRNA is a novel molecular lesion in breast cancer cells, which acts to suppress responsiveness of VDR target genes, resulting in 1a,25(OH) 2 D 3 resistance and seems to be particularly associated with estrogen receptor negativity.This lesion provides a novel molecular diagnostic and can be targeted by combinations of vitamin D 3 compounds and low doses of TSA.The nuclear receptor superfamily regulates diverse signals that are central to the formation and homeostasis of the mammary gland. The postgenomic description of the superfamily conjoined with profiling approaches (1) reveals that breast myoepithelial and epithelial cells express a rich cohort of nuclear receptors, many of which display overt nutrient-sensing capacity for micronutrients and macronutrients alongside the estrogen receptors (ERa and ERh; refs. 2 -6).Several of the diet-sensing nuclear receptors, such as the VDR, preferentially form heterodimers with retinoid X receptors whereas the ERs preferentially heterodimerize with one another. For the nuclear receptors to regulate transcriptional programs, these dimers must be contained as subunits in either large gene coactivator or corepressor complexes. In the absence of ligand, receptors exist in an apo state as part of large complexes (f2.0 MDa; ref. 7), associated with corepressors (e.g., NCoR1, NCoR2/SMRT, and TRIP15/Alien), and bound to response element sequences. These complexes actively recruit a range of enzymes that posttranslationally modify histone tails (e.g., histone deacetylases and methyltransferases) and thereby maintain a locally closed chromatin structure around response element sequences (8). Ligand binding induces a...

show abstract

Section: Methodsmentioning

confidence: 99%

Altered Nuclear Receptor Corepressor Expression Attenuates Vitamin D Receptor Signaling in Breast Cancer Cells

Banwell¹,

MacCartney²,

Guy

et al. 2006

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…: 240-632-4639; Fax: 301-527-4200; E-mail: kinchm@medimmune.com. cells were cultured as described previously (23)(24)(25). Monoclonal antibodies specific for phosphotyrosine (PY20) and ␤-catenin were purchased from Transduction Laboratories (Lexington, KY).…”

Section: Methodsmentioning

confidence: 99%

Regulation of the EphA2 Kinase by the Low Molecular Weight Tyrosine Phosphatase Induces Transformation

Kikawa¹,

Vidale

Etten

et al. 2002

Journal of Biological Chemistry

126

137

View full text Add to dashboard Cite

Intracellular signaling by protein tyrosine phosphorylation is generally understood to govern many aspects of cellular behavior. The biological consequences of this signaling pathway are important because the levels of protein tyrosine phosphorylation are frequently elevated in cancer cells. In the classic paradigm, tyrosine kinases promote tumor cell growth, survival, and invasiveness, whereas tyrosine phosphatases negatively regulate these same behaviors. Here, we identify one particular tyrosine phosphatase, low molecular weight tyrosine phosphatase (LMW-PTP), which is frequently overexpressed in transformed cells. We also show that overexpression of LMW-PTP is sufficient to confer transformation upon non-transformed epithelial cells. Notably, we show that the EphA2 receptor tyrosine kinase is a prominent substrate for LMW-PTP and that the oncogenic activities of LMW-PTP result from altered EphA2 expression and function. These results suggest a role for LMW-PTP in transformation progression and link its oncogenic potential to EphA2.

show abstract

“…For these reasons, they are a widely accepted model of normal human mammary gland epithelium, where the effects of putative breast cancer genes can be assessed (9,10). A second human mammary gland epithelial cell line with similar features but derived from reduction mammoplasty tissue of a different female patient, the MCF-12A cell line (8), and human primary mammary gland epithelial cells subjected to pharmacological inhibition of ATM were also investigated.…”

Section: Ataxia Telangiectasia (A-t)mentioning

confidence: 99%

Ataxia Telangiectasia Mutated (ATM) Inhibition Transforms Human Mammary Gland Epithelial Cells

Mandriota

Buser

Lesne

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Carriers of mutations in the cell cycle checkpoint protein kinase ataxia telangiectasia mutated (ATM), which represent 1-2% of the general population, have an increased risk of breast cancer. However, experimental evidence that ATM deficiency contributes to human breast carcinogenesis is lacking. We report here that in MCF-10A and MCF-12A cells, which are well established normal human mammary gland epithelial cell models, partial or almost complete stable ATM silencing or pharmacological inhibition resulted in cellular transformation, genomic instability, and formation of dysplastic lesions in NOD/ SCID mice. These effects did not require the activity of exogenous DNA-damaging agents and were preceded by an unsuspected and striking increase in cell proliferation also observed in primary human mammary gland epithelial cells. Increased proliferation correlated with a dramatic, transient, and proteasomedependent reduction of p21 WAF1/CIP1 and p27 KIP1 protein levels, whereas little or no effect was observed on p21 WAF1/CIP1 or p27 KIP1 mRNAs. p21 WAF1/CIP1 silencing also increased MCF-10A cell proliferation, thus identifying p21 WAF1/CIP1 down-regulation as a mediator of the proliferative effect of ATM inhibition. Our findings provide the first experimental evidence that ATM is a human breast tumor suppressor. In addition, they mirror the sensitivity of ATM tumor suppressor function and unveil a new mechanism by which ATM might prevent human breast tumorigenesis, namely a direct inhibitory effect on the basal proliferation of normal mammary epithelial cells.

show abstract

Characterization of epithelial phenotypes in mortal and immortal human breast cells

Cited by 90 publications

References 28 publications

Altered Nuclear Receptor Corepressor Expression Attenuates Vitamin D Receptor Signaling in Breast Cancer Cells

Altered Nuclear Receptor Corepressor Expression Attenuates Vitamin D Receptor Signaling in Breast Cancer Cells

Regulation of the EphA2 Kinase by the Low Molecular Weight Tyrosine Phosphatase Induces Transformation

Ataxia Telangiectasia Mutated (ATM) Inhibition Transforms Human Mammary Gland Epithelial Cells

Contact Info

Product

Resources

About