The molecular basis of radiosensitivity and chemosensitivity in the treatment of breast cancer.
The molecular basis of sensitivity to therapeutic radiation and chemotherapy is a complex product of cellular and tissue responses. Certain genetic factors can be highlighted as being of special importance in the response of breast cancers to treatment. The breast cancer susceptibility genes, BRCA1 and BRCA2, determine the phenotype of the tumor, with BRCA1- or BRCA2-deficient tumors showing marked sensitivity to ionizing radiation and drugs that produce double-strand breaks. However, the extent to which loss of BRCA1 or BRCA2 function occurs in sporadic cancer has not yet been determined. The ATM protein plays a significant role in determining the response to therapy, but how frequently the function of ATM is disrupted in breast cancer is debated. Although the p53 protein is a major determinant of the response to ionizing radiation and cytotoxic drugs, there is no consistency in how p53 affects the survival of cells, because an impairment of DNA repair is offset by reduced apoptosis. Growth factors that sustain the proliferation of breast cancer cells may impact the response to therapy by inhibiting apoptosis. Loss of cell-cycle checkpoint responses may result in increased sensitivity, particularly if the checkpoint controls the G2 transition. Overexpression of cyclin D, which shortens the duration of the G1 transition, is associated with mild radiation resistance, perhaps by inhibiting apoptosis. Overall, there is much more to be understood in the complex response of breast cancers to therapy, and many other proteins play important roles in the response to treatment. The focus of our investigation is on those genetic alterations in tumors that affect the response to therapy, which will ultimately allow strategies to achieve therapeutic gain.
Xia
Fen
F
Harvard Medical School, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA.
Powell
Simon N
SN
D001260:Ataxia Telangiectasia; D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy*; D018797:Cell Cycle Proteins; D019938:Cyclin D1 / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins; D004361:Drug Tolerance / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1 / Q000502:physiology; D024522:Genes, BRCA2 / Q000502:physiology; D018734:Genes, erbB-2; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology; D011836:Radiation Tolerance / Q000235:genetics*; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases