Cyclin-dependent kinases as downstream targets of oestrogen action: potential prognostic indicators and therapeutic targets

Sutherland, R. L.; Prall, Owen W.J.; Alle, K M; Wilcken, Nicholas; Hui, Rosaline C.-Y.; Ball, Jonathon; Šarčević, Boris; Henshall, Susan M.; Musgrove, Elizabeth A.; Watts, Colin

doi:10.1677/erc.0.0040357

Cited by 8 publications

(2 citation statements)

References 21 publications

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“…Cyclin D1 interacts both physically and functionally with ER, leading to upregulation of ER-mediated transcription [25]. A strong association between cyclin D1 and ER mRNA levels has been found, suggesting a functional relationship between the expressions of these genes [35]. Other studies have shown that high cyclin D1 levels are associated with ER positivity and/or well-differentiated carcinomas, both features known to be associated with a good prognosis [12,37], consistent with our finding of an association between cyclin D1 expression and ER· expression, which was mainly detected in well-differentiated tumors.…”

Section: Discussionmentioning

confidence: 98%

Expression of Estrogen Receptor-α and Ki67 in Relation to Pathological and Molecular Features in Early-Onset Infiltrating Ductal Carcinoma

Ding¹,

Sheu²,

Yu³

et al. 2004

J Biomed Sci

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Estrogen causes breast cancer by triggering proliferation via an estrogen receptor (ER)-mediated mechanism. However, paradoxically, ERα, one of the two known ER subtypes, and the proliferation marker, Ki67, are not usually expressed in the same breast tumor. To explore whether ERα-positive tumors and proliferating (Ki67-positive) tumors have different tumorigenic characteristics, we performed an immunohistochemical study on 74 early-onset infiltrating ductal carcinomas of the breast. To test this hypothesis, we examined whether ERα-positive and Ki67-positive tumors showed differences in (i) pathological grade, (ii) three indices of tumor grade (tubule formation, nuclear pleomorphism, and mitotic number), and (iii) expression of important proteins implicated in breast tumorigenesis (cyclin D1, ErbB2, ATM, BRCA1, Rb, p53, and p21). The results of the multigenic analysis showed that ERα and Ki67 were the only two important markers significantly and independently associated with tumor grade, consistent with the above hypothesis. ERα- positive, Ki67-negative tumors frequently displayed a low tumor grade (i.e. being well differentiated), whereas Ki67-positive, ERα-negative tumors were more likely to exhibit a high tumor grade. In addition, positive ERα expression (46 of 74 cases, 62%) correlated well with positive cyclin D1 expression (p < 0.005), less nuclear pleomorphism (p < 0.001), and a low mitotic count (p < 0.005), whereas positive Ki67 expression (36 of 74 cases, 49%) correlated with reduced BRCA1 expression (p < 0.01) and high mitotic activity (p < 0.01). These findings suggest that the expressions of ERα and Ki67 might be involved in distinct pathological and molecular features during breast cancer development.

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Section: Discussionmentioning

confidence: 98%

Expression of Estrogen Receptor-α and Ki67 in Relation to Pathological and Molecular Features in Early-Onset Infiltrating Ductal Carcinoma

Ding¹,

Sheu²,

Yu³

et al. 2004

J Biomed Sci

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“…CCND1 expression status might also be a useful marker to predict the response to endocrine therapy (Gillett et al, 1996;Sutherland et al, 1997;Wilcken et al, 1997;Barnes and Gillett, 1998).…”

mentioning

confidence: 99%

Prognostic value of CCND1 gene status in sporadic breast tumours, as determined by real-time quantitative PCR assays

et al. 2002

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The CCND1 gene, a key cell-cycle regulator, is often altered in breast cancer, but the mechanisms underlying CCND1 dysregulation and the clinical significance of CCND1 status are unclear. We used real-time quantitative PCR and RT -PCR assays based on fluorescent TaqMan methodology to quantify CCND1 gene amplification and expression in a large series of breast tumours. CCND1 overexpression was observed in 44 (32.8%) of 134 breast tumour RNAs, ranging from 3.3 to 43.7 times the level in normal breast tissues, and correlated significantly with positive oestrogen receptor status (P=0.0003). CCND1 overexpression requires oestrogen receptor integrity and is exacerbated by amplification at 11q13 (the site of the CCND1 gene), owing to an additional gene dosage effect. Our results challenge CCND1 gene as the main 11q13 amplicon selector. The relapse-free survival time of patients with CCND1-amplified tumours was shorter than that of patients without CCND1 alterations, while that of patients with CCND1-unamplified-overexpressed tumours was longer (P=0.011). Only the good prognostic significance of CCND1-unamplified-overexpression status persisted in Cox multivariate regression analysis. This study confirms that CCND1 is an ER-responsive or ER-coactivator gene in breast cancer, and points to the CCND1 gene as a putative molecular marker predictive of hormone responsiveness in breast cancer. Moreover, CCND1 amplification status dichotomizes the CCND1-overexpressing tumors into two groups with opposite outcomes.

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Cell cycle proteins do not predict outcome in grade I infiltrating ductal carcinoma of the breast

Leong

Hanby

Potts³

et al. 2000

Int. J. Cancer

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Cyclin-dependent kinases as downstream targets of oestrogen action: potential prognostic indicators and therapeutic targets

Cited by 8 publications

References 21 publications

Expression of Estrogen Receptor-α and Ki67 in Relation to Pathological and Molecular Features in Early-Onset Infiltrating Ductal Carcinoma

Expression of Estrogen Receptor-α and Ki67 in Relation to Pathological and Molecular Features in Early-Onset Infiltrating Ductal Carcinoma

Prognostic value of CCND1 gene status in sporadic breast tumours, as determined by real-time quantitative PCR assays

Cell cycle proteins do not predict outcome in grade I infiltrating ductal carcinoma of the breast

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Cyclin-dependent kinases as downstream targets of oestrogen action: potential prognostic indicators and therapeutic targets

Cited by 8 publications

References 21 publications

Expression of Estrogen Receptor-&alpha; and Ki67 in Relation to Pathological and Molecular Features in Early-Onset Infiltrating Ductal Carcinoma

Expression of Estrogen Receptor-&alpha; and Ki67 in Relation to Pathological and Molecular Features in Early-Onset Infiltrating Ductal Carcinoma

Prognostic value of CCND1 gene status in sporadic breast tumours, as determined by real-time quantitative PCR assays

Cell cycle proteins do not predict outcome in grade I infiltrating ductal carcinoma of the breast

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Product

Resources

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Expression of Estrogen Receptor-α and Ki67 in Relation to Pathological and Molecular Features in Early-Onset Infiltrating Ductal Carcinoma

Expression of Estrogen Receptor-α and Ki67 in Relation to Pathological and Molecular Features in Early-Onset Infiltrating Ductal Carcinoma