17q12-21 - the pursuit of targeted therapy in breast cancer.
OBJECTIVE
Identification of HER2/neu, and the subsequent development of targeted therapy for patients who over-express it, has revolutionized their management. Research has since focused on the area of chromosome 17 in which HER2/neu is located in order to identify other genes in the vicinity. The aims of this review are, firstly, to discuss current thinking in relation to the role of these genes in the pathogenesis of breast cancer and, secondly, to examine how this evidence may be assimilated such that new forms of targeted therapy can be developed.


METHODS
This review discusses the evidence in relation to 4 genes located at the HER2/neu amplicon, namely TOP2A, GRB7, STARD3 and RARA.


RESULTS
TOP2A has aroused particular interest as over-expression of its protein has been shown to correlate, both with amplification of HER2/neu, and with response to anthracycline-based chemotherapeutic agents in breast cancer. GRB7 is included on Oncotype DXtm, and has recently been implicated in gastric and oesophageal cancer. STARD3 and RARA also hold clinical relevance, the former having been shown to function in steroidogenesis and therefore implicated in hormone-receptor-positive breast cancer. Finally, RARA may be the key to unlocking the problem of resistance to all-trans retinoic acid (ATRA) in breast cancer sufferers; this treatment has previously been demonstrated to induce remission in over 80% of patients with acute promyelocytic leukaemia (APML).


CONCLUSIONS
These genes hold potential as therapeutic targets, and warrant further investigation as we move towards our goal of individually tailored therapeutic strategies in breast cancer.
Glynn
R W
RW
Department of Surgery, Clinical Science Institute, National University of Ireland, Costello Road, Galway, Ireland. ronanglynn@doctors.org.uk
Miller
N
N
Kerin
M J
MJ
D000951:Antigens, Neoplasm / Q000502:physiology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D002352:Carrier Proteins / Q000502:physiology; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D004250:DNA Topoisomerases, Type II / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology; D005260:Female; D051382:GRB7 Adaptor Protein / Q000502:physiology; D018390:Gene Targeting; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology; D000075223:Poly-ADP-Ribose Binding Proteins; D018168:Receptors, Retinoic Acid / Q000502:physiology; D000072482:Retinoic Acid Receptor alpha
D000951:Antigens, Neoplasm; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C495955:GRB7 protein, human; D008565:Membrane Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; C105684:STARD3 protein, human; D051382:GRB7 Adaptor Protein; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human