Abstract
IntroductionDuring the menstrual cycle, the mammary gland goes through sequential waves of proliferation and apoptosis. In mammary epithelial cells, hormonal and non-hormonal factors regulate apoptosis. To determine the cyclical effects of gonadal steroids on breast homeostasis, we evaluated the apoptotic index (AI) determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining in human mammary epithelial cells during the spontaneous menstrual cycle and correlated it with cellular proliferation as determined by the expression of Ki-67 during the same period.MethodsNormal breast tissue samples were obtained from 42 randomly selected patients in the proliferative (n = 21) and luteal (n = 21) phases. Menstrual cycle phase characterization was based on the date of the last and subsequent menses, and on progesterone serum levels obtained at the time of biopsy.ResultsThe proliferation index (PI), defined as the number of Ki-67-positive nuclei per 1,000 epithelial cells, was significantly larger in the luteal phase (30.46) than in the follicular phase (13.45; P = 0.0033). The AI was defined as the number of TUNEL-positive cells per 1,000 epithelial cells. The average AI values in both phases of the menstrual cycle were not statistically significant (P = 0.21). However, the cell renewal index (CRI = PI/AI) was significantly higher in the luteal phase (P = 0.033). A significant cyclical variation of PI, AI and CRI was observed. PI and AI peaks occurred on about the 24th day of the menstrual cycle, whereas the CRI reached higher values on the 28th day.ConclusionsWe conclude that proliferative activity is dependent mainly on hormonal fluctuations, whereas apoptotic activity is probably regulated by hormonal and non-hormonal factors.
Highlights
During the menstrual cycle, the mammary gland goes through sequential waves of proliferation and apoptosis
To clarify the cyclical effects of gonadal steroids on breast homeostasis, we evaluated the apoptotic index (AI) in human mammary epithelial cells (by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining [11]) during the spontaneous menstrual cycle and correlated it with cellular proliferation as determined by Ki-67 expression [12] during the same period
transferasemediated dUTP nick end labeling (TUNEL)-positive cells from representative patients for each group are given in Fig. 1C–E; Fig. 1f shows a highly magnified TUNEL-positive cell displaying the characteristic features of chromatin condensation and apoptotic bodies
Summary
The mammary gland goes through sequential waves of proliferation and apoptosis. To determine the cyclical effects of gonadal steroids on breast homeostasis, we evaluated the apoptotic index (AI) determined by terminal deoxynucleotidyl transferasemediated dUTP nick end labeling (TUNEL) staining in human mammary epithelial cells during the spontaneous menstrual cycle and correlated it with cellular proliferation as determined by the expression of Ki-67 during the same period. Understanding the factors and mechanisms that regulate hormone-related changes in the normal human breast is crucial, because alterations in breast structure and function during the menstrual cycle could predispose this tissue to malignant changes and to the development of breast cancer. AI = apoptotic index; CRI = cell renewal index; EGFR = epidermal growth factor receptor; ER = estrogen receptor; PBS = phosphate-buffered saline; PI = proliferation index; TdT = terminal deoxynucleotidyl transferase; TUNEL = TdT-mediated dUTP nick end labeling
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