Low-molecular-weight cyclin E can bypass letrozole-induced G1 arrest in human breast cancer cells and tumors.
OBJECTIVE
Low-molecular-weight cyclin E (LMW-E) in breast cancer cells induces genomic instability and resistance to inhibition by p21, p27, and fulvestrant therapy. Here, we sought to determine if LMW-E renders breast cancer cells unresponsive to aromatase inhibitors (AI), elucidate the mechanism of such resistance, and ascertain if inhibitors of LMW-E-associated kinase activity could overcome this resistance.


METHODS
The antiproliferative effects of the AIs were examined in aromatase-overexpressing MCF-7/Ac1 cells in the presence or absence of full-length cyclin E and LMW-E. Inhibition of LMW cyclin E kinase activity by roscovitine [a cyclin-dependent kinase (CDK) inhibitor] was examined in letrozole-unresponsive MCF-7/Ac1 cells. The role of LMW-E and CDK2 in mediating recurrence following AI treatment was also assessed in breast cancer patients.


RESULTS
Overexpression of LMW-E in postmenopausal patients was associated with a poor prognosis. Letrozole, but not exemestane or anastrozole, mediated a pronounced G(1) arrest in MCF-7/Ac1 cells. Androstenedione-induced G(1) exit correlated with increased cyclin E-associated kinase activity and increased CDK2 levels. Letrozole treatment inhibited cyclin E-CDK2 kinase activity by preventing the androstenedione-induced increase in CDK2. LMW-E bypassed this effect and rendered the cells resistant to letrozole inhibition. Roscovitine blocked the androstenedione-induced increase in CDK2, and LMW-E overexpression could not bypass this effect. Lastly, breast cancer patients whose tumors overexpress LMW-E were not responsive to AI treatment.


CONCLUSIONS
Roscovitine treatment can reverse intrinsic or acquired resistance to letrozole due to LMW-E expression in breast cancer cells. These data support the clinical investigation of CDK2 inhibitor therapy for postmenopausal women with estrogen receptor-positive, LMW-E-expressing breast cancer.
Akli
Said
S
Departments of Experimental Radiation Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas 77030, USA. sakli@mdanderson.org
Bui
Tuyen
T
Wingate
Hannah
H
Biernacka
Anna
A
Moulder
Stacy
S
Tucker
Susan L
SL
Hunt
Kelly K
KK
Keyomarsi
Khandan
K
D047072:Aromatase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D019927:Cyclin E / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005260:Female; D016193:G1 Phase; D006801:Humans; D000077289:Letrozole; D008970:Molecular Weight; D009570:Nitriles / Q000494:pharmacology; D017698:Postmenopause; D011379:Prognosis; D011687:Purines / Q000494:pharmacology*; D000077546:Roscovitine; D014230:Triazoles / Q000494:pharmacology
D047072:Aromatase Inhibitors; D019927:Cyclin E; D009570:Nitriles; D011687:Purines; D014230:Triazoles; D000077546:Roscovitine; D000077289:Letrozole