Involvement of G1/S cyclins in estrogen-independent proliferation of estrogen receptor-positive breast cancer cells

Abstract

Estrogen receptor-mediated transcription is enhanced by overexpression of G1/S cyclins D1, E or A in the presence as well in the absence of estradiol. Excess of G1/S cyclins also prevents the inhibition of transactivation of estrogen receptor (ER) by the pure antiestrogen ICI 182780. Cyclin D1 mediates this transactivation independent of complex formation to its CDK4/6 partner. This raises the possibility that overexpression of G1/S cyclins renders growth of ER-positive breast cancer hormone-independent and resistant to treatment with antiestrogens. Transient transfection of ER-positive breast cancer cell lines T47D and MCF7 with G1/S cyclins could overcome the growth arrest induced by ICI 182780 treatment. The ability of various cyclin D1 mutants to overcome the ICI 182780 mediated growth arrest corresponded with their ability to stimulate cyclin A-and E2F-promoter based reporter activities in the presence of ICI 182780. Transfection of a mutant cyclin D1 (cyclin D1-KE) that was unable to bind CDK4 and was reported to transactivate ER in the presence of ICI 182780, could not stimulate proliferation in ICI 182780 treated cells. On the other hand, cyclin D1-LALA, which is unable to stimulate ERE transactivation, could overcome the ICI 182780 cell cycle arrest. Furthermore, transient transfection of T47D cells using cyclin D1 together with a catalytic inactive mutant of CDK4 (CDK4-DN) indicated that the observed effect is due to binding to CDK inhibitors. However, a moderate, sixfold overexpression of cyclin D1 in stably transfected MCF7 cells did not overcome the ICI 182780 mediated growth arrest. These results indicate that CDK-independent transactivation of the estrogen receptor by cyclin D1 is by itself, not sufficient to result in estradiol-independent growth of breast cancer cells, whereas a vast overexpression of G1/S cyclins is able to do so, most likely by capturing of CDK inhibitors.

The retinoblastoma tumor suppressor modifies the therapeutic response of breast cancer

“…Our studies suggest that cyclin D1 gene upregulation or protein overexpression (data not shown) fail to predict Tam response. This is consistent with several studies that have shown that cyclin D1 levels do not stringently correlate with Tam resistance (51,52). Although our studies are modeling immunohistochemical loss of RB, disruption of RB transcriptional repression can occur through additional mechanisms that could also contribute to Tam resistance.…”

Impaired p53 function leads to centrosome amplification, acquired ERα phenotypic heterogeneity and distant metastases in breast cancer MCF-7 xenografts

“…Likewise, cyclin E/cdk2 and cyclin A/cdk2 complexes are responsible for the G 1 /S transition and onset of DNA replication, respectively (Hwang and Clurman, 2005;Mailand and Diffley, 2005). Aberrant expression of cyclins is linked to breast cancer development and progression (Bindels et al, 2002;Akli et al, 2004;Caldon et al, 2006). While cyclin D1 overexpression is generally associated with an ERapositive phenotype and favorable clinical outcome, deregulation of cyclin E and A is linked to induction of centrosome amplification, aneuploidy, loss of ERa and poor outcome (Bindels et al, 2002;Span et al, 2003;Joe et al, 2005).…”

“…Aberrant expression of cyclins is linked to breast cancer development and progression (Bindels et al, 2002;Akli et al, 2004;Caldon et al, 2006). While cyclin D1 overexpression is generally associated with an ERapositive phenotype and favorable clinical outcome, deregulation of cyclin E and A is linked to induction of centrosome amplification, aneuploidy, loss of ERa and poor outcome (Bindels et al, 2002;Span et al, 2003;Joe et al, 2005). One mechanism for preservation of genomic stability is through p53-mediated control of centrosome homeostasis (Fukasawa, 2005).…”

Cyclin-E is a strong predictor of endocrine therapy failure in human breast cancer

“…To establish this predictive value of cyclin-E, only prospective studies with randomization to endocrine treatment could yield irrefutable results. The involvement of cyclin-E with breast cancer prognosis has been attributed to its association with cell cycle regulation and cellular proliferation (Ku¨hling et al, 2003), chromosomal instability (Spruck et al, 1999), or (anti) estrogen-independent growth (Bindels et al, 2002;Dhillon and Mudryj, 2002). Our results strongly indicate that the latter mechanism is of physiological importance in breast cancer.…”