Genetic and Epigenetic Changes in Mammary Epithelial Cells May Mimic Early Events in Carcinogenesis

Tlsty, Thea D.; Crawford, Yongping; Holst, Charles R.; Fordyce, Colleen; Zhang, Jianmin; McDermott, Kimberly M.; Kozakiewicz, Krystyna; Gauthier, Mona L.

doi:10.1023/b:jomg.0000048773.95897.5f

Cited by 79 publications

(64 citation statements)

References 44 publications

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“…In a majority of ducts and lobules including TDLU in normal mammary tissues, cytokeratins 5/6 and 17 were expressed in both basal and luminal cells, confi rming the previously described variability of expression of these basal cytokeratins and their relationship to cellular origin 30 . Cytokeratin 5 and 17 have also been found in a subset of breast cancer patients with a poor clinical outcome 32 .…”

Section: Discussionsupporting

confidence: 83%

Novel Immunohistochemical Markers for the Differentiation of Lobular and Ductal Invasive Breast Carcinomas

Turashvili¹,

Bouchal²,

Ehrmann³

et al. 2007

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Aims. Invasive ductal and lobular carcinomas are the most common histological types of breast cancer. The loss of E-cadherin expression has been suggested to be the most reliable marker for invasive lobular carcinoma. The aim of our study was to identify the diagnostic usefulness of novel markers in the diff erentiation of these tumor types.Methods. We examined tissue microarrays (TMA) which were constructed from surgical specimens of 119 breast cancer patients. TMA consisted of 80 ductal carcinomas, 29 lobular carcinomas and special type cancers. TMA sections were stained using standard immunohistochemical methods. Monoclonal mouse antibodies against E-cadherin, cytokeratin 5/6 and 17, and polyclonal mouse antibodies against EMP1, DDR1, PRKCI and DVL1 were used.Results. E-cadherin was absent in 93.3 % of lobular tumors compared with only 15 % of ductal tumors (p < 0.0001). EMP1 and DVL1 were overexpressed in lobular tumors (93.1 % and 96.5 %, respectively), whereas PRKCI and DDR1 were positive in ductal cancers (90 % and 96.2 %, respectively). Reduced expression or absence of both cytokeratins 5/6 and 17 was found in both tumor tissues in comparison to normal terminal duct lobular units (p < 0.0001).Conclusions. Apart from the well-established marker, E-cadherin, proteins examined on TMA slides by immunohistochemistry (EMP1, DVL1, DDR1, PRKCI) may represent novel tissue markers helpful in the diff erentiation of ductal and lobular breast cancers. Further studies with larger sets of patients are desirable, to verify the complete immunohistochemical profi les of various histological types of breast cancer and determine the prognostic and predictive signifi cance of novel markers. BACKGROUND

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Section: Discussionsupporting

confidence: 83%

Novel Immunohistochemical Markers for the Differentiation of Lobular and Ductal Invasive Breast Carcinomas

Turashvili¹,

Bouchal²,

Ehrmann³

et al. 2007

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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“…These advances in the knowledge of the breast methylome strongly indicate that DNA hypermethylation plays a crucial role in initiation, promotion and maintenance of breast carcinogenesis, which cooperatively and synergistically interact with other genetic alterations to promote the development of breast cancer. For example, human mammary epithelial cells (HMECs) that gained the ability to emerge from the first transient growth plateau lost p16INK4A expression concurrently with hypermethylation of p16INK4A promoter, indicating that loss of tumor-suppressor function of p16INK4A is required for HMECs to gain growth competency by successfully bypassing the stage of cell senescence Tlsty et al, 2004). This finding is consistent with other studies where the life span of stem cells could be extended by germline loss of this gene (Janzen et al, 2006).…”

Section: Epigenetic Modifications and Breast Cancersupporting

confidence: 86%

Epigenetics and Breast Cancer

Alokail¹

2011

Breast Cancer - Focusing Tumor Microenvironment, Stem Cells and Metastasis

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“…We and others have previously shown that the silencing and DNA methylation of the p16 INK4A locus occurs during selection (9,10,(12)(13)(14)(15), and it has been suggested that epigenetic deregulation of p16 INK4A occurs commonly in premalignant breast lesions. Indeed, rare foci of morphologically normal epithelial cells with hypermethylation of the tumor suppressor gene p16 INK4A have been identified in vivo in disease-free breast tissue (12) and these foci have been hypothesized to be precursors to cancer (16).…”

Section: Introductionmentioning

confidence: 99%

Concordant Epigenetic Silencing of Transforming Growth Factor-β Signaling Pathway Genes Occurs Early in Breast Carcinogenesis

et al. 2007

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Human mammary epithelial cells (HMEC) grown under standard cell culture conditions enter a growth phase referred to as selection, but a subpopulation is able to escape from arrest and continue to proliferate. These cells, called postselection or variant HMECs, may be derived from progenitor cells found in normal mammary epithelium that subsequently acquire premalignant lesions, including p16 INK4A promoter hypermethylation. Epigenetic silencing of tumor suppressor genes through DNA methylation and histone modification is an early event in tumorigenesis. A major challenge is to find genes or gene pathways that are commonly silenced to provide early epigenetic diagnostic and therapeutic cancer targets. To identify very early epigenetic events that occur in breast cancer, we used microarrays to screen for gene pathways that were suppressed in post-selection HMECs but reactivated after treatment with the demethylation agent 5-aza-2 ¶-deoxycytidine. We found that several members of the transforming growth factor B (TGF-b) signaling pathway were consistently down-regulated in the post-selection HMEC populations, and this was associated with a marked decrease in Smad4 nuclear staining. Gene suppression was not associated with DNA methylation but with chromatin remodeling, involving a decrease in histone H3 lysine 27 trimethylation and an increase in histone H3 lysine 9 dimethylation and deacetylation. These results show for the first time that TGF-b2, its receptors TGF-bR1 and TGF-bR2, and activator thrombospondin-1 are concordantly suppressed early in breast carcinogenesis by histone modifications and indicate that the TGF-b signaling pathway is a novel target for gene activation by epigenetic therapy.

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Genetic and Epigenetic Changes in Mammary Epithelial Cells May Mimic Early Events in Carcinogenesis

Cited by 79 publications

References 44 publications

Novel Immunohistochemical Markers for the Differentiation of Lobular and Ductal Invasive Breast Carcinomas

Novel Immunohistochemical Markers for the Differentiation of Lobular and Ductal Invasive Breast Carcinomas

Epigenetics and Breast Cancer

Concordant Epigenetic Silencing of Transforming Growth Factor-β Signaling Pathway Genes Occurs Early in Breast Carcinogenesis

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