Downstream targets of growth factor and oestrogen signalling and endocrine resistance: the potential roles of c-Myc, cyclin D1 and cyclin E.
Antioestrogen therapy is a highly effective treatment for patients with oestrogen-receptor (ER)-positive breast cancer, emphasising the central role of oestrogen action in the development and progression of this disease. However, effective antioestrogen treatment is often compromised by acquired endocrine resistance, prompting the need for a greater understanding of the down-stream mediators of oestrogen action that may contribute to this effect. Recent studies have demonstrated a critical link between oestrogen's mitogenic effects and cell cycle progression, particularly at the G1 to S transition where key effectors of oestrogen action are c-Myc and cyclin D1, which converge on the activation of cyclin E-cdk2. These components are rapidly upregulated in response to oestrogen, and can mimic its actions on cell cycle progression, including re-initiating cell proliferation in antioestrogen-arrested cells. Here we review the roles of c-Myc, cyclin D1 and cyclin E in oestrogen action and endocrine resistance, and identify their potential as markers of disease progression and endocrine responsiveness, and as novel therapeutic targets in endocrine-resistant breast cancer.
Butt
Alison J
AJ
Cancer Research Program, Garvan Institute of Medical Research, St Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia.
McNeil
Catriona M
CM
Musgrove
Elizabeth A
EA
Sutherland
Robert L
RL
D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019938:Cyclin D1 / Q000502:physiology*; D019927:Cyclin E / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D019927:Cyclin E; D004965:Estrogen Antagonists; D004967:Estrogens; D006133:Growth Substances; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D011960:Receptors, Estrogen; D019938:Cyclin D1