Altered expression of cyclin E and the retinoblastoma protein influences the effect of adjuvant therapy in breast cancer

Abstract

Abstract. Cyclin E and the retinoblastoma protein (Rb) are both important regulators of the G 1 phase in the cell cycle. Overexpression of cyclin E and lost expression of Rb has previously been observed in breast tumours at frequencies of 10-50% and 20-30%, respectively. We explored the prognostic role of cyclin E and Rb in breast cancer patients randomised for tamoxifen (TAM), CMF (cyclophosphamide, metotrexate, 5-fluorouracil) chemotherapy and radiotherapy (RT) and how their expression affects the patients' response to treatment. Protein expression was assessed with immunohistochemistry. We found overexpression of cyclin E in 32.1% (71/221) of the tumours and loss of Rb expression in 25.0% (59/236). Increased expression of cyclin E correlated to dysfunctional p53 (P=0.003) while loss of Rb correlated to normal p53 status (P=0.001). Our results suggest that patients with high cyclin E tumours have less benefit from tamoxifen (ER+, TAM vs. no TAM; RR=0.97; 95% CI, 0.36-2.60) than patients whose tumours show low expression (ER+, TAM vs. no TAM; RR =0.41; 95% CI,. Cyclin E also tended to predict the benefit from radiotherapy with a local recurrence rate of 0.31 (RT vs. CMF; 95% CI, 0.12-0.83) for patients with low expression and 0.68 (RT vs. CMF; 95% CI, 0.2-2.32) for patients with high expression of cyclin E. When the p53 status was taken in consideration the results showed that patients with both normal p53 and normal Rb expression had considerably lower locoregional recurrence rate when treated with radiotherapy instead of CMF (RR=0.17; 95% CI, 0.052-0.58) as compared to patients with either altered Rb or p53 or both (RR=0.70; 95% CI, 0.28-1.73).

A non-functional retinoblastoma tumor suppressor (RB) pathway in premenopausal breast cancer is associated with resistance to tamoxifen

“…Other studies related to RB status and prognosis have focused on the basal levels of RB but, interestingly, they also report a lack of association between RB expression and recurrence rate. 12,14,24 Out of the 57 patients with a non-functional RB pathway, only 12 were ER + and subsequently included in the analysis …”

P16 but not retinoblastoma expression is related to clinical outcome in no-special-type triple-negative breast carcinomas

“…[11][12][13][14] Rb immunohistochemistry studies have provided conflicting results concerning prognosis and response to therapies, and also because of the use of different immunohistochemistry cutoff. 10,[14][15][16][17][18][19][20] The results reported by Derenzini et al 16 indicated that only the absence but not hyperphosphorylation of Rb protein predicts clinical outcome. However, it should be noted that immunohistochemistry expression of Rb has provided contradictory interpretations concerning correlation with RB1 gene status.…”

“…13,14,16,18,20,25,31 However, only few studies focused this issue in triple-negative breast carcinomas.…”

“…[11][12][13][14] Unfortunately, immunohistochemistry studies showing a decrease in or lack of Rb protein expression have provided conflicting results concerning prognosis and response to therapies. 10,[14][15][16][17][18][19][20] Rb is inactivated by cyclin-dependent kinase (CDK)4-mediated phosphorylation, and the kinase activity of CDK4 is suppressed by p16INK4a (p16). Because inactivation of Rb results in the upregulation of p16 expression, high levels of p16 were used as an immunohistochemistry surrogate of Rb loss, mainly in squamous cell carcinomas harboring high-risk papilloma virus.…”

Whether to target single or multiple CDKs for therapy? That is the question

“…Overexpression of cyclins, the regulatory subunits, occurs more frequently in tumors. Amplification of cyclin D, cyclin E, and cyclin B1 reported in leukemia and lymphomas and in a number of solid tumors like breast cancer might also have a prognostic value (Waltersson et al, 2009) and seem to be associated with poor prognosis (Ko et al, 2009). Finally, inactivation or loss of cellular inhibitors of CDKs during carcinogenesis or their aberrant regulation are very frequent events occurring in human cancer.…”