Elsevier

The Breast

Volume 13, Issue 6, December 2004, Pages 452-460
The Breast

Review
Radioresistance in carcinoma of the breast

https://doi.org/10.1016/j.breast.2004.08.004Get rights and content

Summary

Radiotherapy plays an important role in the management of breast cancer. Whilst its role in achieving local control following surgery in patients with early stage cancer is well established, there is still unclear evidence to explain the factors governing radioresistance in patients who develop recurrences both in the breast and axilla. Radiotherapy induces damage to the DNA. Various cell cycle damage check points and DNA damage repair pathways have been demonstrated. Ataxia telangiectasia mutant (ATM) kinase, which is a member of phosphatidylinositol-3 kinase (PI-3K) family appears to play a central role in DNA damage check point pathways. Over-expression of Insulin like growth factor-I receptor (IGF-IR), Human Epidermal Growth factor receptors (HERS), Vascular Endothelial growth factor (VEGF) on the cell surface and increased concentration of Epidermal Growth factor in the extracellular fluid have been associated with radioresistance. Specific genes such as p53, BRCA, Bcl-2 and chromosomal characteristics like telomere lengths have also been identified as playing significant roles in radiation responsiveness of a cell. This article reviews the current data on general principles of radiotherapy, the cellular mechanisms that operate in response to radiation damage and various molecular markers, intranuclear and extranuclear which have been demonstrated to influence radiation sensitivity in breast cancer cells.

Introduction

Breast cancer is one of the commonest solid neoplasms and accounts for 1 in 3 of all female cancers. In the UK over 40,000 women are now diagnosed annually with breast cancer,1 and this trend is likely to continue for some time to come. However, more women are being successfully treated than ever before with three out of four surviving for five years or more. With improvements in treatment and the success of the National screening programme, mortality rates have reduced significantly. Around 13,000 women died of breast cancer in 2001, a decrease of 21% over the last decade.1 It is now recognized that breast cancer is a systemic disease, which originates in the breast but has more widespread manifestations. Hence therapies such as surgery and radiotherapy are used to achieve local control and systemic treatments (chemotherapy, immunotherapy, hormonal therapy) are used to alter the systemic milieu and attack distant metastatic cells. Local and systemic therapies are not necessarily used sequentially, but are mixed to maximise benefits and minimise risks according to the needs of the patient.

Radiotherapy has become a recognized treatment modality for selected breast cancer patients. It is now considered mandatory for most patients undergoing conservative surgery and is considered appropriate for women at high risk of recurrence after mastectomy. Randomized controlled trials have demonstrated that radiotherapy to the breast after a wide local excision (WLE) for localized ductal carcinoma in situ (DCIS) and to early invasive cancers and radiotherapy to axilla in node-positive invasive cancers have significantly reduced the incidence of local recurrences.2, 3, 4, 5, 6 However, in patients who develop recurrence of their disease, the functional mechanisms behind resistance of cells to radiotherapy remains largely elusive. Studies have shown that among the patients who develop recurrences after a WLE and radiotherapy for DCIS, at least half of them will have invasive cancer with its concomitant risk of metastasis and death.7, 8 Hence the need for better understanding on the biology of radioresistance in breast cancer cells. Various factors, extranuclear and intranuclear (Fig. 1) have been identified to be influencing radiation responsiveness of cells. Here we review some general concepts related to radiotherapy, cellular mechanisms that occur in response to radiation and the available information in the literature on the molecular and genetic aspects of radioresistance in breast cancer cells.

Section snippets

Methods

A Pubmed search was performed from its inception till date for all papers using the keywords ‘Breast cancer’ and ‘Radioresistance’. An additional search was also performed on Medline for articles related to DCIS of breast; Breast cancer incidence; Markers and recurrences.

General concepts on radiotherapy

Radiotherapy is the therapeutic use of ionizing radiation for the treatment of malignant disorders. The source of ionizing radiation may be radioactive isotopes or external beam radiotherapy. Radioactive isotopes can be used either locally at the tumour site (iridium needles for carcinoma of tongue) or systemically (iodine –131 for carcinoma of thyroid).9 External beam radiotherapy is more commonly used in breast cancer. This involves delivery of high energy X-rays to the target tissue. These

Cellular responses to radiotherapy

Cell cycle for proliferating cells is composed of four phases —S (DNA synthesis), M (mitosis) and the gaps before and after S phase, G1 and G2, respectively. Cells that are not proliferating are said to be in G0 phase or resting phase. The most radiosensitive phase of the cell cycle is the M phase. Growth fraction in a tumour refers to the proportion of cells, which are in proliferation. Accordingly, the higher the growth fraction, greater number of cells in proliferation and hence more cell

Insulin-like growth factor-I receptor (IGF-IR)

IGF-IR is a tyrosine kinase, transmembrane receptor expressed in almost all body tissues. It has been extensively studied and is found to be an important regulator of cell growth, differentiation, transformation and apoptosis and has been implicated in breast cancer development.18 In oestrogen receptor (ER)-positive breast tumors, the levels of the IGF-IR and its substrate, insulin-receptor substrate-1 (IRS-1) are often elevated and these characteristics have been linked with increased

p53

Mutations in this gene located on chromosome 17p are the most common genetic alterations in human primary breast carcinoma. p53 plays a pivotal role in multiple cellular processes such as cell growth control and apoptosis. p53 mutations are associated with worse prognosis and with chemo/radioresistance, due to the inability to trigger p53-dependent apoptosis.39 An analysis of the p53 gene was performed by Marchetti et al. in 13 consecutive high-risk primary breast cancer (HR-BC) patients with

Conclusion

Although there are numerous experimental studies performed in an attempt to understand better the mechanisms involved in mediating radioresistance in breast cancer cells, there are currently no clear cut guidelines in clinical practice to differentiate the breast cancer patients who would respond to radiotherapy from those who would not, based on any specific molecular or genetic marker. Also the studies in the literature have only addressed the issue of radioresistance in invasive breast

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