Gap Junction Distribution and Connexin Expression in Human Breast

Monaghan, Paul; Clarke, Catherine; Perusinghe, Nina; Moss, D. W.; Chen, Xiaoyuan; Evans, William Howard

doi:10.1006/excr.1996.0055

Cited by 65 publications

(62 citation statements)

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“…Cx26 and Cx43 are disparately expressed in the breast-luminal cells express Cx26 while myoepithelial cells express Cx43 [14]. Although the luminal and basal breast cancer subtypes arise from these two different cell types, there was no association between connexin expression and ER/PR/Her2 status, and therefore breast cancer subtype (Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…In the breast, connexin 26 (Cx26) is expressed by luminal cells while connexin 43 (Cx43) is expressed by myoepithelial cells [14]. Loss of Cx26 and Cx43 has been shown to correlate with tumor progression in breast and colorectal cancer and over-expression of Cx43 reduces breast cancer metastasis [15][16][17].…”

Section: Expression Of Gap Junction Proteins Is Increased In Breast Cmentioning

confidence: 99%

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Partial Mesenchymal to Epithelial Reverting Transition in Breast and Prostate Cancer Metastases

Chao

Acquafondata

et al. 2011

Cancer Microenvironment

142

140

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Epithelial to mesenchymal transition (EMT) is an oft-studied mechanism for the initiation of metastasis. We have recently shown that once cancer cells disseminate to a secondary organ, a mesenchymal to epithelial reverting transition (MErT) may occur, which we postulate is to enable metastatic colonization. Despite a wealth of in vitro and in vivo studies, evidence supportive of MErT in human specimens is rare and difficult to document because clinically detectable metastases are typically past the micrometastatic stage at which this transition is most likely evident. We obtained paired primary and metastatic tumors from breast and prostate cancer patients and evaluated expression of various epithelial and mesenchymal markers by immunohistochemistry. The metastases exhibited increased expression of membranous E-cadherin compared to primary tumors, consistent with EMT at the primary site and MErT at the metastatic site. However, the re-emergence of the epithelial phenotype was only partial or incomplete. Expression of epithelial markers connexins 26 and/or 43 was also increased on the majority of metastases, particularly those to the brain. Despite the upregulation of epithelial markers in metastases, expression of mesenchymal markers vimentin and FSP1 was mostly unchanged. We also examined prostate carcinoma metastases of varied sizes and found that while E-cadherin expression was increased compared to the primary lesion, the expression inversely correlated with size of the metastasis. This not only suggests that a second EMT may occur in the ectopic site for tumor growth or to seed further metastases, but also provides a basis for the failure to discern epithelial phenotypes in clinically examined macrometastases. In summary, we report increased expression of epithelial markers and persistence of mesenchymal markers consistent with a partial MErT that readily allows for a second EMT at the metastatic site. Our results suggest that cancer cells continue to display phenotypic plasticity beyond the EMT that initiates metastasis.

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Section: Discussionmentioning

confidence: 99%

Section: Expression Of Gap Junction Proteins Is Increased In Breast Cmentioning

confidence: 99%

Partial Mesenchymal to Epithelial Reverting Transition in Breast and Prostate Cancer Metastases

Chao

Acquafondata

et al. 2011

Cancer Microenvironment

142

140

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“…A decrease or loss of Cxs expression has also been reported [6,11]. In normal human breast tissue, Cx26 is localized to the membranes of luminal cells, whereas epithelial cells of benign lesions and lobular carcinoma do not express Cx26 [5,11]. In addition, Conklin et al [6] reported that Cx43 is downregulated at various stages of breast cancer progression, including ductal carcinomas in situ, infiltrating ductal carcinoma and infiltrating lobular carcinomas.…”

mentioning

confidence: 88%

“…Cxs have been previously reported in various types of malignant tumors, including breast, liver, colon, and esophageal tumors [5][6][7][8][9][10]. A decrease or loss of Cxs expression has also been reported [6,11].…”

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confidence: 89%

Altered Expression and Localization of Connexin32 in Human and Murine Gastric Carcinogenesis

et al. 2010

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Background Intercellular communication via gap junctions, composed of protein subunits called connexins (Cxs), plays a key role in controlling cell growth, differentiation and carcinogenesis. Impaired gap junctional intercellular communication has been reported in various cancers and diseases. Aims We investigated Cx32 expression patterns and semiquantitatively assessed Cx32 expression in cancers and preneoplastic lesions. To determine if cell proliferation is correlated with Cx32 expression, we evaluated Ki67 expression in a gastric cancer mouse model. Methods In human and mouse, normal stomach and gastric adenocarcinoma tissues were used for immunohistochemical analyses.Results Cx32 was detected at cell-cell (intercellular) contact points in normal cells and exhibited punctate intercellular and intracytoplasmic staining in cancer cells. The frequency of Cx32 loss of expression was significantly higher in human adenocarcinomas than in normal stomach. As tumor cells were less differentiated, Cx32 expression levels and intercellular and intracytoplasmic staining were also significantly lower. The Cx32 expression pattern in the mouse gastric cancer model was similar in several important respects to that of human. In mucous metaplasia of the mouse stomach, Cx32 was mainly expressed in the cytoplasm of epithelial cells. There was also an inverse correlation between Cx32 expression and cell proliferation in mouse tumors. However, there was no difference in the levels of Cx32 mRNA between normal and cancerous tissues. Conclusions These findings suggest that altered Cx32 expression, a loss of intercellular Cx32 and a gain of intracytoplasmic Cx32 in the form of punctate ''dot'', plays an important role in the formation of gastric adenocarcinomas.

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“…In the mouse, gap junctions composed of Cx26, Cx30 or Cx32 have been identified between mammary luminal cells, whereas Cx43 gap junctions were found to be more restricted to myoepithelial cells and stromal fibroblasts (El-Sabban et al, 2003). Similarly, in human breast epithelium, Cx26 has been localized to luminal cells, whereas Cx43 is mainly present between myoepithelial cells, but has been reported to be expressed in luminal cells as well (Monaghan et al, 1996;Laird et al, 1999). Although connexins were first proposed as tumor suppressors more than two decades ago (Lee et al, 1991(Lee et al, , 1992, their role in breast cancer is still poorly understood and somewhat controversial.…”

Section: Introductionmentioning

confidence: 99%

Cx43 suppresses mammary tumor metastasis to the lung in a Cx43 mutant mouse model of human disease

et al. 2010

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Gap junctions, the channels formed by the connexin (Cx) family of proteins, are responsible for direct intercellular communication. Although connexins are considered as tumor suppressors, their overall role in cancer onset, progression and metastasis is somewhat controversial. This study uses a novel Cx43 mutant mouse model (G60S mice) and cross-breeding strategies to determine the role of Cx43 in all stages of breast tumorigenesis. G60S mice were cross-bred with ErbB2 overexpressing mice, and spontaneous and 7,12-dimethylbenz[a]anthracene (DMBA)-induced tumor development was evaluated. Mice were killed when tumors reached B1 cm 3 or when mice showed signs of critical illness. In both spontaneous and DMBA studies, onset of palpable tumors was delayed in G60S mice compared with mice in control groups. Moreover, while tumors from control mice reached the size threshold, most DMBA-exposed Cx43 mutant mice were killed prematurely because of labored breathing, independent of the presence of a palpable tumor. Reduced Cx43 levels in Cx43 mutant mice were accompanied by extensive mammary gland hyperplasia. Lung histology revealed that all Cx43 mutant mice exhibited mammaglobin-positive mammary gland metastases to the lung, and the number of metastases was increased by threefold in Cx43 mutant mice on treatment with DMBA. Thus, while reduced levels of Cx43 delayed the onset of palpable tumors, normal Cx43 levels inhibited mammary gland tumor metastasis to the lungs. Understanding the mechanisms of how Cx43, which is expressed primarily in myoepithelial cells, inhibits mammary gland tumor metastasis is critical as Cx43 is assessed as a candidate for therapeutic intervention.

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Gap Junction Distribution and Connexin Expression in Human Breast

Cited by 65 publications

References 0 publications

Partial Mesenchymal to Epithelial Reverting Transition in Breast and Prostate Cancer Metastases

Partial Mesenchymal to Epithelial Reverting Transition in Breast and Prostate Cancer Metastases

Altered Expression and Localization of Connexin32 in Human and Murine Gastric Carcinogenesis

Cx43 suppresses mammary tumor metastasis to the lung in a Cx43 mutant mouse model of human disease

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