Increased exposure to estrogen is associated with an elevated risk of breast cancer. Considering estrogen as a possible mutagen, we hypothesized that exposure to estrogen alone or in combination with the DNA-damaging chemotherapy drug, cisplatin, could induce expression of genes encoding enzymes involved in APOBEC-mediated mutagenesis. To test this hypothesis, we measured the expression of APOBEC3A (A3A) and APOBEC3B (A3B) genes in two breast cancer cell lines treated with estradiol, cisplatin, or their combination. These cell lines, T-47D (ER+) and MDA-MB-231 (ER-), differed by the status of the estrogen receptor (ER). Expression of A3A was not detectable in any conditions tested, while A3B expression was induced by treatment with cisplatin and estradiol in ER+ cells but was not affected by estradiol in ER- cells. In The Cancer Genome Atlas (TCGA), expression of A3B was significantly associated with genotypes of a regulatory germline variant rs17000526 upstream of the APOBEC3 cluster in 116 ER- breast tumors (p= 0.006) but not in 387 ER+ tumors (p= 0.48). In conclusion, we show that in breast cancer cell lines, A3B expression was induced by estradiol in ER+ cells and by cisplatin regardless of ER status. In ER+ breast tumors, the effect of estrogen may be masking the association of rs17000526 with A3B expression, which was apparent in ER- tumors. Our results provide new insights into the differential etiology of ER+ and ER- breast cancer and the possible role of A3B in this process through a mitogenic rather than the mutagenic activity of estrogen.
Published by Oxford University Press 2020.
APOBEC3A Is a Prominent Cytidine Deaminase in Breast CancerLM Cortez et al. PLoS Genet 15 (12), e1008545. PMID 31841499.APOBEC cytidine deaminases are the second-most prominent source of mutagenesis in sequenced tumors. Previous studies have proposed that APOBEC3B (A3B) is the major source …
APOBEC3B High Expression Status Is Associated With Aggressive Phenotype in Japanese Breast CancersM Tsuboi et al. Breast Cancer 23 (5), 780-8. PMID 26476745.The expression of A3B in breast cancer was higher than in non-cancerous tissues and was related to the lymph node metastasis and nuclear grade, which are reliable aggress …
Integrative Genomic Analysis Reveals Functional Diversification of APOBEC Gene Family in Breast CancerY Zhang et al. Hum Genomics 9, 34. PMID 26682542.These results suggest that functional potential of APOBEC3B and APOBEC3C involved in cancer mutagenesis is associated with ER status.
Genotoxic Metabolites of Estradiol in Breast: Potential Mechanism of Estradiol Induced CarcinogenesisW Yue et al. J Steroid Biochem Mol Biol 86 (3-5), 477-86. PMID 14623547. - ReviewLong term exposure to estradiol increases the risk of breast cancer in a variety of animal species, as well as in women. The mechanisms responsible for this effect have n …
Estrogen Mediation of Breast Tumor Formation Involves Estrogen Receptor-Dependent, as Well as Independent, Genotoxic EffectsR Santen et al. Ann N Y Acad Sci 1155, 132-40. PMID 19250200. - ReviewLong-term exposure to estrogens influences the development of breast cancer in women, but the precise mechanisms involved are not clearly defined. Our working hypothesis …