title: Altered radiation responses of breast cancer cells resistant to hormonal therapy.
abstract: Endocrine therapy agents (the selective estrogen receptor (ER) modulators such as tamoxifen or the selective ER down-regulators such as ICI 182,780) are key treatment regimens for hormone receptor-positive breast cancers. While these drugs are very effective in controlling ER-positive breast cancer, many tumors that initially respond well to treatment often acquire drug resistance, which is a major clinical problem. In clinical practice, hormonal therapy agents are commonly used in combination or sequence with radiation therapy. Tamoxifen treatment and radiotherapy improve both local tumor control and patient survival. However, tamoxifen treatment may render cancer cells less responsive to radiation therapy. Only a handful of data exist on the effects of radiation on cells resistant to hormonal therapy agents. These scarce data show that cells that were resistant to tamoxifen were also resistant to radiation. Yet, the existence and mechanisms of cross-resistance to endocrine therapy and radiation therapy need to be established. Here, we for the first time examined and compared radiation responses of MCF-7 breast adenocarcinoma cells (MCF-7/S0.5) and two antiestrogen resistant cell lines derived from MCF-7/S0.5: the tamoxifen resistant MCF-7/TAMR-1 and ICI 182,780 resistant MCF-7/182R-6 cell lines. Specifically, we analyzed the radiation-induced changes in the expression of genes involved in DNA damage, apoptosis, and cell cycle regulation. We found that the tamoxifen-resistant cell line in contrast to the parental and ICI 182,780-resistant cell lines displayed a significantly less radiation-induced decrease in the expression of genes involved in DNA repair. Furthermore, we show that MCF-7/TAMR-1 and MCF-7/182R-6 cells were less susceptible to radiation-induced apoptosis as compared to the parental line. These data indicate that tamoxifen-resistant breast cancer cells have a reduced sensitivity to radiation treatment. The current study may therefore serve as a roadmap to the future analysis of the mechanisms of cross-resistance between hormonal therapy and radiation.
authors: Department of Biological Sciences, University of Lethbridge, University Drive, Lethbridge, AB, Canada.
authors: Lidiya
authors: L
authors: Luzhna
authors: Breast Cancer Group, Cell Death and Metabolism, Danish Cancer Society Research Center, Strandboulevarden, Copenhagen, Denmark.
authors: Anne E
authors: AE
authors: Lykkesfeldt
authors: Department of Biological Sciences, University of Lethbridge, University Drive, Lethbridge, AB, Canada.
authors: Olga
authors: O
authors: Kovalchuk
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy*; D004249:DNA Damage; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000528:radiation effects; D019008:Drug Resistance, Neoplasm; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000528:radiation effects; D015894:Genome, Human / Q000528:radiation effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D010766:Phosphorylation / Q000528:radiation effects; D011836:Radiation Tolerance; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D004273:DNA, Neoplasm; D004965:Estrogen Antagonists; C468783:H2AX protein, human; D006657:Histones; D013629:Tamoxifen