Identification of functional transport in non lactating breast epithelium and its relationship to parity and menstrual cycle.

Abstract

Abstract Abstract #4084 Background: The electrophysiological properties of breast epithelia have not been extensively studied in non-lactating women. Furthermore, it is known that parity is protective against breast cancer, but it is unknown how parity may influence the functional characteristics of breast epithelia and whether there is a carry over effect after childbirth.
 Patients and Methods: With IRB and patient consent, electrical contact with ductal epithelium was established non-invasively, using a specially designed nipple sensor in 15 normal women under the age of 40 with no risk factors for breast cancer. The transepithelial potential (TEP) and resistance of the skin were abolished with sonopheresis. TEP was measured across the breast epithelium using an isolated millivoltmeter. In a separate study isolated mammary epithelial cells were obtained from 14 women undergoing surgery to identify the origins of transepithelial potential in non-lactating epithelia. Cultures were established in media permissive for epithelial cells, which were immunomagnetically purified and mounted on porous substrates. Ion transport was measured in an Ussing chamber coupled to a voltage clamp apparatus. Data were analyzed using t-test, Mann-Whitney test, or ANOVA as appropriate.
 Results: Nulliparous women (n=8) had an open circuit potential of -56 ± 2 mV (mean ± SEM), -55 ± 1 mV, -56 ± 2 mV and -57 ± 2 mV during weeks 1-4 for 64 observations weekly through 2 complete menstrual cycles. Parous women (n=7) had open circuit potentials which were hyperpolarized compared to nulliparous women with values of -64 ± 1 mV (p < 0.001), -65 ± 1 mV (p < 0.001), -60 ± 2 mV (p n.s.) and -63 ± 2 mV (p<0.005) during weeks 1-4 for 56 observations weekly through 2 menstrual cycles. Therefore the transepithelial potential was 6-10 mV hyperpolarized in parous women compared to nulliparous women except in the 3rd week of menstrual cycle. Primary cultures of human mammary epithelial cells, which thrived in culture and matured successfully into competent (> 200 Ω.cm2) monolayers (50%), upregulated transepithelial ion movement in response to adrenergic stimulus (10uM norepinephrine). These currents were sensitive to pharmacologic inhibitors of ENaC (electrogenic sodium transport), NKCC (Na,K,2Cl) and Na/K ATPase. These findings suggest electrogenic sodium and chloride transport are responsible for the TEP observed in vivo. Post partum modulation of the activity of one of these functioning elements identified in non-cancerous monolayers may be responsible for the observed differences in TEP observed in this study.
 Discussion: Parity appears to make the epithelium functionally competent so that it maintains a higher transepithelial potential, and is “primed for lactation”. Depolarization of the epithelium throughout cycle (as in the nulliparous group) may make it more susceptible to proliferative signals. Epithelial depolarization may represent a biomarker of breast cancer risk, the ionic basis of which remains to be elucidated. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4084.