Enhancement of genomic instability by 17βestradiol in minisatellite sequences of X-ray-transformed mouse 10T1/2 cells

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Abstract
The female hormone 17β-estradiol is involved in the development of breast cancer, an effect usually attributed to its capacity to stimulate the replication of preneoplastic and malignant cells. In this study, we report that 17β-estradiol enhances the onset of genomic rearrangements, a type of genomic instability, in minisatellite sequences of malignant 10T1½2 mouse cells. Two malignant clones, X-ray-9 and F-17a, previously transformed in vitro by X-rays (600 cGYS), and two non-transformed 10T1½2 mouse cell subclones (10T1½2b and 10T1½2c)were divided into two groups. The first group was incubated in the presence of 10-5 M of 17β-estradiol (dissolved in ethanol) for 5 days, while the second group was incubated for the same period in culturemedia containing 0.1% of ethanol. After the incubation both groups of cells were then subcloned, and their DNA was extracted and analyzedwith the DNA fingerprinting assay using the Probe M (core sequence: 5'-AGGC).A high frequency og genomic rearrangements was observed in the transformed subclones treated with 17β-estradiol. Nine deletions or additionsin minisatellite alleles were observed in six F-17a subclones, while 28 of those genomic rearrangements were found in the 12 X-ray-9 malignant subclones. On the other hand, for the non-transformed 10T1½2b and 10T1½2c cells, no genomic rearrangements were induced by the hormone. After the withdrawl of 17β-estradiol from the transformed clone X-ray-9, no newgenomic rearrangements were detected; while a second incubation with the hormoneinduced new deletions or additions in minisatellite alleles. This preferential enhancement of genomic instability in malignanat 10T1½2 mouse cells suggests that17β-estradiol may accelerate the accumation of mutations, and therefore may represent a mechanism by which the female hormone contributes to breast cancer development.

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