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Aberrant c-erbB2 expression in cell clusters overlying focally disrupted breast myoepithelial cell layers: a trigger or sign for emergence of more aggressive cell clones?

Zhang X, Hashemi SS, Yousefi M, Ni J, Wang Q, Gao L, Gong P, Gao C, Sheng J, Mason J, Man YG - Int. J. Biol. Sci. (2008)

Bottom Line: Of 448 FMCLD detected, 404 (90.2%) were associated with cell clusters that had intense c-erbB2 immunoreactivities primarily in their cytoplasm, in contrast to their adjacent counterparts within the same duct, which had no or barely detectable c-erbB2 expression.Molecular assays detected markedly higher c-erbB2 mRNA and gene amplification in cell clusters associated with FMCLD than in those associated with non-disrupted ME cell layers.Our findings suggest that cell clusters overlying FMCLD may represent the precursors of pending invasive lesions, and that aberrant c-erbB2 expression may trigger or signify the emergence of biologically more aggressive cell clones.

View Article: PubMed Central - PubMed

Affiliation: College of Animal Science and Veterinary Medicine, Jilin University, Changchun, Jilin, China.

ABSTRACT
Our recent studies revealed that cell clusters overlying focal myoepithelial cell layer disruption (FMCLD) had a significantly higher frequency of genetic instabilities and expression of invasion-related genes than their adjacent counterparts within the same duct. Our current study attempted to assess whether these cell clusters would also have elevated c-erbB2 expression. Human breast tumors (n=50) with a high frequency of FMCLD were analyzed with double immunohistochemistry, real-time RT-PCR, and chromogenic in situ hybridization for c-erbB2 protein and gene expression. Of 448 FMCLD detected, 404 (90.2%) were associated with cell clusters that had intense c-erbB2 immunoreactivities primarily in their cytoplasm, in contrast to their adjacent counterparts within the same duct, which had no or barely detectable c-erbB2 expression. These c-erbB2 positive cells were arranged as tongue-like projections, "puncturing" into the stroma, and about 20% of them were in direct continuity with tube-like structures that resembled blood vessels. Aberrant c-erbB2 expression was also seen in clusters of architecturally normal-appearing ducts that had distinct cytological abnormalities in both ME and epithelial cells, whereas not in their clear-cut normal counterparts. Molecular assays detected markedly higher c-erbB2 mRNA and gene amplification in cell clusters associated with FMCLD than in those associated with non-disrupted ME cell layers. Our findings suggest that cell clusters overlying FMCLD may represent the precursors of pending invasive lesions, and that aberrant c-erbB2 expression may trigger or signify the emergence of biologically more aggressive cell clones.

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Aberrant c-erbB2 expression in normal-appearing duct clusters. Human breast tissue sections were double immunostained for c-erbB2 (brown or black) and smooth muscle actin (red). Arrows identify examples of ducts with aberrant c-erbB2 expression. Note that a majority of the ducts in some duct clusters are strongly positive for c-erbB2, whereas all ducts in other duct clusters are devoid of c-erbB2 expression. a, c, e, and g: 100X; b, d, f, and h: a higher magnification (300X) of a, c, e, and g, respectively.
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Figure 3: Aberrant c-erbB2 expression in normal-appearing duct clusters. Human breast tissue sections were double immunostained for c-erbB2 (brown or black) and smooth muscle actin (red). Arrows identify examples of ducts with aberrant c-erbB2 expression. Note that a majority of the ducts in some duct clusters are strongly positive for c-erbB2, whereas all ducts in other duct clusters are devoid of c-erbB2 expression. a, c, e, and g: 100X; b, d, f, and h: a higher magnification (300X) of a, c, e, and g, respectively.

Mentions: In addition to DCIS and hyperplastic lesions, elevated expression of c-erbB2 was detected in large clusters of morphologically normal-appearing ducts in 7 cases. The numbers of ducts per cluster ranged from 10 to over 50 (Fig 3). Under low magnification, these duct clusters were architecturally comparable to their adjacent normal counterparts. Under high magnification, the ME cell layers in a vast majority of these ducts were attenuated, discontinuous, or totally absent. The epithelial cells of these normal-appearing duct clusters often displayed distinct cytological abnormalities, including enlarged and irregular-shaped nuclei, increased nuclear-cytoplasmic ratio, and substantially enlarged nucleoli, similar to those described in our previous report 8. Similar to c-erbB2 positive malignant and hyperplastic cells, these c-erbB2 positive normal-appearing cells were also arranged as tongue-like projections “puncturing” deep into the stroma (Fig 3). These normal appearing duct clusters had a distinct boundary with adjacent counterparts that lacked c-erbB2 expression and had non-disrupted ME cell layers (Fig 3).


Aberrant c-erbB2 expression in cell clusters overlying focally disrupted breast myoepithelial cell layers: a trigger or sign for emergence of more aggressive cell clones?

Zhang X, Hashemi SS, Yousefi M, Ni J, Wang Q, Gao L, Gong P, Gao C, Sheng J, Mason J, Man YG - Int. J. Biol. Sci. (2008)

Aberrant c-erbB2 expression in normal-appearing duct clusters. Human breast tissue sections were double immunostained for c-erbB2 (brown or black) and smooth muscle actin (red). Arrows identify examples of ducts with aberrant c-erbB2 expression. Note that a majority of the ducts in some duct clusters are strongly positive for c-erbB2, whereas all ducts in other duct clusters are devoid of c-erbB2 expression. a, c, e, and g: 100X; b, d, f, and h: a higher magnification (300X) of a, c, e, and g, respectively.
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Related In: Results  -  Collection

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Figure 3: Aberrant c-erbB2 expression in normal-appearing duct clusters. Human breast tissue sections were double immunostained for c-erbB2 (brown or black) and smooth muscle actin (red). Arrows identify examples of ducts with aberrant c-erbB2 expression. Note that a majority of the ducts in some duct clusters are strongly positive for c-erbB2, whereas all ducts in other duct clusters are devoid of c-erbB2 expression. a, c, e, and g: 100X; b, d, f, and h: a higher magnification (300X) of a, c, e, and g, respectively.
Mentions: In addition to DCIS and hyperplastic lesions, elevated expression of c-erbB2 was detected in large clusters of morphologically normal-appearing ducts in 7 cases. The numbers of ducts per cluster ranged from 10 to over 50 (Fig 3). Under low magnification, these duct clusters were architecturally comparable to their adjacent normal counterparts. Under high magnification, the ME cell layers in a vast majority of these ducts were attenuated, discontinuous, or totally absent. The epithelial cells of these normal-appearing duct clusters often displayed distinct cytological abnormalities, including enlarged and irregular-shaped nuclei, increased nuclear-cytoplasmic ratio, and substantially enlarged nucleoli, similar to those described in our previous report 8. Similar to c-erbB2 positive malignant and hyperplastic cells, these c-erbB2 positive normal-appearing cells were also arranged as tongue-like projections “puncturing” deep into the stroma (Fig 3). These normal appearing duct clusters had a distinct boundary with adjacent counterparts that lacked c-erbB2 expression and had non-disrupted ME cell layers (Fig 3).

Bottom Line: Of 448 FMCLD detected, 404 (90.2%) were associated with cell clusters that had intense c-erbB2 immunoreactivities primarily in their cytoplasm, in contrast to their adjacent counterparts within the same duct, which had no or barely detectable c-erbB2 expression.Molecular assays detected markedly higher c-erbB2 mRNA and gene amplification in cell clusters associated with FMCLD than in those associated with non-disrupted ME cell layers.Our findings suggest that cell clusters overlying FMCLD may represent the precursors of pending invasive lesions, and that aberrant c-erbB2 expression may trigger or signify the emergence of biologically more aggressive cell clones.

View Article: PubMed Central - PubMed

Affiliation: College of Animal Science and Veterinary Medicine, Jilin University, Changchun, Jilin, China.

ABSTRACT
Our recent studies revealed that cell clusters overlying focal myoepithelial cell layer disruption (FMCLD) had a significantly higher frequency of genetic instabilities and expression of invasion-related genes than their adjacent counterparts within the same duct. Our current study attempted to assess whether these cell clusters would also have elevated c-erbB2 expression. Human breast tumors (n=50) with a high frequency of FMCLD were analyzed with double immunohistochemistry, real-time RT-PCR, and chromogenic in situ hybridization for c-erbB2 protein and gene expression. Of 448 FMCLD detected, 404 (90.2%) were associated with cell clusters that had intense c-erbB2 immunoreactivities primarily in their cytoplasm, in contrast to their adjacent counterparts within the same duct, which had no or barely detectable c-erbB2 expression. These c-erbB2 positive cells were arranged as tongue-like projections, "puncturing" into the stroma, and about 20% of them were in direct continuity with tube-like structures that resembled blood vessels. Aberrant c-erbB2 expression was also seen in clusters of architecturally normal-appearing ducts that had distinct cytological abnormalities in both ME and epithelial cells, whereas not in their clear-cut normal counterparts. Molecular assays detected markedly higher c-erbB2 mRNA and gene amplification in cell clusters associated with FMCLD than in those associated with non-disrupted ME cell layers. Our findings suggest that cell clusters overlying FMCLD may represent the precursors of pending invasive lesions, and that aberrant c-erbB2 expression may trigger or signify the emergence of biologically more aggressive cell clones.

Show MeSH
Related in: MedlinePlus