Effects of estrogen on cell cycle progression and associated metabolic pathways in normal and tumorigenic breast cells

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Abstract
Estrogens are widely used in hormone replacement therapies but their actions particularly in combination with other hormones are poorly understood. Incubation of human MCF‐7 breast cancer cells with high doses of 17β‐estradiol demonstrated changes in morphology such as detachment of the adherent population and an accumulation in G2/M phase of the cell cycle within 24 h. Continuous treatment of MCF‐7 cells with up to 10 μM 17β‐estradiol every 24 h was also associated with the appearance of about 20% cell death in subG1 phase. Interestingly, MCF‐7 cells in G2/M phase following continuous incubation with 10 nM to 1 μM 17β‐estradiol returned to control cell cycle distributions with no significant cell death in subG1 after 96 h, respectively. These findings suggested an estrogen concentration‐dependent sensitivity of MCF‐7 cells. In contrast, incubation of normal human breast epithelial cells (HMEC‐1) with similar amounts of 17β‐estradiol did not result in any significant change in morphology and G2/M phase distribution, respectively, and continuous exposure of HMEC‐1 with up to 10 μM 17β‐estradiol demonstrated less than 5% of apoptotic subG1 populations. Investigations of short term signals revealed a significantly increased 20S proteasomal proteolytic activity which was dependent on poly(ADP‐ribose)polymerase in estrogen‐stimulated MCF‐7 tumor cells within 60 min. In contrast, there was little if any detectable change in this proteolytic activity in HMEC‐1 following estrogen treatment. Moreover, while expression levels of manganese superoxide dismutase and the matrix metalloproteinase MMP‐9 remained unchanged in MCF‐7 cells and HMEC‐1 during estrogen treatment, respectively, the amount of MMP‐1 and MMP‐7 significantly increased in the MCF‐7 tumor cells within 60 min after estrogen exposure. In contrast, MMP‐7 protein expression was progressively reduced in HMEC‐1 in an estrogen concentration‐dependent manner within 60 min. Taken together, these findings suggest different estrogen‐mediated signaling mechanisms in normal human breast epithelial cells when compared to their tumorigenic counterparts. Consequently, the distinct threshold effects of estrogen in vitro allow a certain signaling selectivity and may thus question the significance of an overall standard dose used in hormone replacement therapy.