Mechanisms of breast cancer resistance to chemotherapy

Jonathan A.F. Hannay, Dihua Yu

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

With the advent and evolution of the era of molecular research into cancer, the hallmark of cancer has been conclusively established as the failure of cancer cells to repair and maintain the integrity of their genome. It is generally true that in this respect breast cancer is a clonal disease arising from one aberrant cell having dysregulated growth-control signals. However, within the expanding population of daughter cells there is ever greater heterogeneity in terms of accumulated mutations in the inherited background parent genome. Naturally, each subsequent round of cell division accelerates the destabilization of the genome which, in turn, expresses itself in greater derangements of cellular biology, ultimately leading to the emergence of the most feared phenotype: that of the metastatic cancer cell. Metastases, however, can be controlled if the metastatic cancer cells respond to the cytotoxic effects of chemotherapy and other therapeutics. Unfortunately, in the clinical setting, the most dreadful aspect of cancer is the emergence of a resistant population from amongst the metastatic cancer cells to current therapeutics in the clinician's armamentarium. The chemoresistant phenotype, a function of cancer cells and not of normal tissue, can be viewed as both an acquired and an intrinsic property of cancer cells, reflecting the developmental history of tumors in general [1]. Cancers inherently sensitive to chemotherapy usually have a rapid onset with a few genetic 'hits', typically involving dominant acting oncogenes. The genome of such cancers is relatively stable, with cytogenetic analysis revealing translocation events to have taken place, for example the EWS-ETS translocation in Ewing's sarcoma and c-myc-immunoglobulin locus translocations in Burkitt's lymphoma [2]. Such tumors are often encountered in the pediatric oncology setting. In contrast, tumors presenting with a high degree of chemoresistance have often followed a protracted premalignant course, allowing accumulation of multiple genetic hits to perturb both tumor suppressor genes and oncogenes. Cytogenetic analysis shows complex abnormalities, with diverse karyotypes reflecting a highly unstable genome [2]. Such tumors are typically encountered in the adult oncology setting where, in lung cancer for example, a relatively chemoresistant tumor emerges following chronic exposure to a carcinogen. In these instances a 'field change' of multiple genetic hits can be detected throughout the nonmalignant tissue in which the tumor arises [3]. The chemoresistant phenotype in cancer manifests itself in the clinic as one of three treatment response patterns following agent administration. These patterns are typical for each general type of cancer: those that are intrinsically sensitive and exhibit large-scale cytoreduction and frequent cures following chemotherapy, those that are initially highly responsive but usually relapse and become refractory, and those that have a high degree of intrinsic resistance and respond poorly to chemotherapy from the outset. Breast cancers generally show the second pattern of response to therapy and it is common for patients to relapse a few years after therapy and develop resistant recurrent cancer, or even to develop chemoresistance during treatment. Since single-agent chemotherapy has been shown in randomized trials to be inferior to combination chemotherapy against breast cancer [4-6], most modern anti-breast-cancer chemotherapeutic strategies involve anthracycline- or alkylating- agent-based combination chemotherapy with the addition of antimetabolites, anthraquinones, vinca alkaloids, and taxanes (Table 36.1). Investigations into the mechanisms of emergence of the chemoresistant phenotype have traditionally involved studies using unicellular models exposed to incremental doses of chemotherapeutic agent, with consequent selection for resistant clones. These in vitro studies have led to the identification and functional characterization of many resistance mechanisms and, although these model systems are open to the twin deception of a pharmacocentric outlook and neglect of the role of tumor microenvironment in selection, the information garnered has been verified in animal studies and tumor samples from patients. From the wealth of such studies, and amongst the plethora of changes that can occur within tumor cells, the general strategies that tumor cells employ to elude cytotoxicity are empirically: decreased drug uptake, increased drug extrusion, alterations in the drug target, alterations in drug metabolism, repair of DNA damage, alteration of cell-cycle checkpoint control, and changes in downstream mediators of apoptosis. Each of these mechanisms is discussed below, although neither in a comprehensive nor exhaustive manner. Oncogene (2003) Volume 22, Number 47 contains excellent recent reviews with more in-depth coverage of each of the mechanisms dealt with and would be a good starting point for further information. Figure 36.1 has been adapted from Gary Kruh's introductory article therein [1] (Table presented) (Figure presented).

Original languageEnglish (US)
Title of host publicationBreast Cancer and Molecular Medicine
PublisherSpringer Berlin Heidelberg
Pages783-803
Number of pages21
ISBN (Print)3540282653, 9783540282655
DOIs
StatePublished - 2006

ASJC Scopus subject areas

  • General Medicine

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