|
Estradiol and its metabolites are genotoxic in human breast epithelial cells In the work of Russo’s laboratory at
the Fox Chase Cancer Center in Philadelphia, published in the
International Journal of Cancer they demonstrated that neoplastic
transformation of human breast epithelial cells (MCF-10F cells) with 17
beta estradiol (E2) and its metabolites was accompanied by loss of
heterozygosity in D13S893 located at 13q12.3 and a TP53 5bp deletion found
between codons 98 and 100.
The relevance of these findings is that E2 and its
metabolites induced genomic changes that were not abrogated by the pure
antiestrogen ICI182780 and were not observed in BP-transformed cells,
indicating that the effect observed was specific for E2 and its
metabolites. This indicates that estrogen is genotoxic in human breast
epithelial cells and that the effect is specific and independent of the
estrogen receptor. A further implication of this work is that explain for
the first time in the human breast that estrogen are able to induce
genomic changes inducing neoplastic transformation. Altogether the data
provides rational basis for the reported effect of estrogen in the
increase incidence of breast cancer in women under hormone replacement
therapy. The data have shown that
4-OHE2 and E2 at the doses of 0.007 nM and 70 nM,
and 2-OHE2 only at a higher concentration (3.6 µM) produced a
5bp deletion in TP53, exon 4. The tumor suppressor gene TP53
located on 17p13 is one of the most commonly mutated genes in all types of
human cancer. TP53 is a
critical regulator of cell growth, differentiation, and apoptosis through
its actions in cell cycle checkpoint control. Wild-type TP53 responds to DNA
damage or checkpoint failure by either arresting the cell in the G1 phase
of the cell cycle for damage repair or eliminating the damaged cells
through the initiation of an apoptotic pathway. The TP53 5bp deletion found between
codons 98 and 100 could affect mainly the DNA binding domain and probably
other domains due to a different structure of the protein. One important finding reported here is that E2 and 4-OHE2 are mutagenic even at the lowest dose used, whereas 2-OHE2 transformed cells manifested these mutations only at the highest dose utilized. This observation is supported by data in animal models, in which 4-OHE2 had carcinogenic effect equal to E2, whereas 2-OHE2 did not induce kidney tumors in hamsters and had much less ability to induce uterine adenocarcinomas in CD-1 mice than 4-OHE2. Furthermore, the formation of depurinating adducts at the N-3 of Ade and N-7 of Gua by reaction of E2-3,4-Q or enzyme-catalyzed oxidation of 4-OHE2 with DNA is much higher than that from reaction of E2-3,4-Q enzyme-catalyzed oxidation of 2-OHE2 with DNA. Altogether, this supports the concept that E2 and mainly its metabolite 4-OHE2 are carcinogenic in breast epithelial cells.
Bibliographical reference:
Jose Russo Breast Cancer Research Laboratory, Fox Chase Cancer Center, Philadelphia, PA, USA
|