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Flavonoids and connexin proteins : growth suppression and prognostic value in human breast cancer Conklin, Christopher M. J.


Connexin proteins form gap junctions permitting direct intercellular cytoplasmic exchange. Gap junctional intercellular communication (GJIC) is important for maintaining homeostasis and preventing cell transformation. Connexins may also have independent functions including tumor growth suppression. Most tumors express less connexins, have reduced GJIC, and have increased growth rates compared to nontumorigenic cells. Asian females, who consume foods rich in flavonoids have a 4 to 6-fold reduction in breast cancer incidence. The purpose of this study was to determine if common flavonoids, genistein and quercetin, increase connexin43 (Cx43), improve GJIC, and retard growth of metastatic human breast cancer cells (MDA-MB-231). Results demonstrated that genistein and quercetin are potential anti-breast cancer agents. Although flavonoid treatment did not improve GJIC, genistein (2.5 ug/ml, 5 ug/ml, 15 ug/ml) and quercetin (2.5 |J.g/ml, 5 |a.g/ml) increased Cx43 protein and suppressed MDA-MB-231 cell proliferation at concentrations which were not toxic to nontumorigenic breast cancer cells. Reliable prognostic indicators of breast cancer include axillary nodal status, tumor size and histological grade. Additionally, estrogen receptor/progesterone receptor (ER/PR) status, and Ki67, an indicator of proliferative activity, are useful for predicting patient survival and relapse. Improved prognostic methods and a search for a more complete understanding of cancer biology inspires the identification of new molecular markers. Tissue microarrays, containing over 300 cases of invasive breast carcinoma were stained with Cx26, Cx32, and Cx43 antibodies. Connexin immunoreactivity was correlated with established immunohistochemical and histopathological breast cancer markers. Cx26, Cx32, and Cx43 did not correlate with tumor grade or tumor size. Cx32 inversely correlated with lymph node status (P < 0.05), and there was a positive correlation between Cx43 and PR status (P < 0.01). Both Cx32 and Cx43 correlated positively with ER status (P < 0.01), and Cx43 correlated negatively with Ki67 expression (P < 0.01). Cx26, Cx32, and Cx43 did not correlate with patient outcome. In conclusion, connexin proteins did not appear to be reliable independent indicators of breast cancer prognosis. However, Cx32 may protect against regional lymph node spread, and Cx43 may counteract aggressively proliferating breast cancer.

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