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Clinical Cancer Research 14, 1976, April 1, 2008. doi: 10.1158/1078-0432.CCR-07-4100
© 2008 American Association for Cancer Research
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Human Cancer Biology

Familial Breast Cancers without Mutations in BRCA1 or BRCA2 Have Low Cyclin E and High Cyclin D1 in Contrast to Cancers in BRCA Mutation Carriers

Kirsimari Aaltonen1,2, Carl Blomqvist1,5, Rose-Marie Amini6, Hannaleena Eerola1,2, Kristiina Aittomäki3, Päivi Heikkilä4 and Heli Nevanlinna2

Authors' Affiliations: Departments of 1 Oncology, 2 Obstetrics and Gynaecology, 3 Clinical Genetics, and 4 Pathology, Helsinki University Central Hospital, Helsinki, Finland; and 5 Departments of Oncology, Radiology, and Clinical Immunology and 6 Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden

Requests for reprints: Kirsimari Aaltonen, Department of Oncology, Helsinki University Central Hospital, P.O. Box 180, FIN 00029 HUS, Finland. Phone: 358-9-4711; Fax: 358-9-47173181; E-mail: kirsimari.aaltonen{at}helsinki.fi.


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: We analyzed the expression of critical cell cycle regulators cyclin E and cyclin D1 in familial breast cancer, focusing on BRCA mutation–negative tumors. Cyclin E expression in tumors of BRCA1 or BRCA2 carriers is higher, and cyclin D1 expression lower, than in sporadic tumors. In familial non-BRCA1/2 tumors, cyclin E and cyclin D1 expression has not been studied.

Experimental Design: Cyclin E and cyclin D1 immunohistochemical expression was studied in tissue microarrays consisting of 53 BRCA1, 58 BRCA2, 798 familial non-BRCA1/2, and 439 sporadic breast tumors.

Results: In univariate analysis, BRCA1 tumors had significantly more frequently high cyclin E (88%) and low cyclin D1 (84%) expression than sporadic (54% and 49%, respectively) or familial non-BRCA1/2 (38% and 45%, respectively) tumors. BRCA2 tumors had significantly more frequently low cyclin D1 expression (68%) than sporadic or familial non-BRCA1/2 tumors and significantly more frequently high cyclin E expression than familial non-BRCA1/2 tumors. In a logistic regression model, cyclin expression, early age of onset, and estrogen receptor (ER) and human epidermal growth factor receptor-2 (HER2) status were the independent factors most clearly distinguishing tumors of BRCA1 mutation carriers from other familial breast cancers. High cyclin E and low cyclin D1 expression were also independent predictors of BRCA2 mutation when compared with familial non-BRCA1/2 tumors. Most interestingly, lower frequency of high cyclin E expression independently distinguished familial non-BRCA1/2 tumors also from sporadic ones.

Conclusions: Cyclin E and cyclin D1 expression distinguishes non-BRCA1/2 tumors from both sporadic and BRCA1- and BRCA2-associated tumors and may reflect different predisposition and pathogenesis in these groups.

High-penetrance predisposition genes cause 5% to 10% of breast cancer. The two major high-penetrance susceptibility genes BRCA1 and BRCA2 account together for ~20% of familial breast cancers in Finland (1). Cancers in carriers of BRCA1 and BRCA2 mutations differ from sporadic and familial non-BRCA1/2 cancers. BRCA1-associated tumors are of higher tumor grade; more often estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) negative, and p53 positive; and more often of medullary histology than sporadic cancers (2–6).

cDNA expression analysis suggests that the basal cell epithelial phenotype is overrepresented in tumors of BRCA1 mutation carriers (7). This phenotype has high grade, is ER/PR/HER2 negative, often of typical or atypical medullar histology, and expresses cytokeratin 5/6, cyclin E, and epidermal growth factor receptor (8–10). Expression of basal keratins cytokeratin 14 and cytokeratin 5/6, together with ER status, seems to be predictive for BRCA1 mutation status compared with sporadic breast tumors (11).

In most studies to date, BRCA2-associated tumors have shown a phenotype between the BRCA1-associated and sporadic tumors (4, 5, 12). cDNA studies, however, identify a distinct expression profile for BRCA2 tumors (13).

Most familial breast cancers probably arise from mutations in other, still largely unknown, genes. Little is known about the characteristics of the familial non-BRCA1/2 tumors. They seem to be of lower grade than BRCA1/2-associated or sporadic tumors (6, 14) and more frequently ER and PR positive and p53 negative than BRCA1 tumors (15). The most frequent histologic subtype is invasive ductal carcinoma (6, 14, 15). HER2 expression and amplification is low (15). Based on the expression of 60 different genes, a recent cDNA study (16) divided non-BRCA1/2 tumors into two groups that differed in aggressiveness.

The cell cycle regulators cyclin E and cyclin D1 mediate positive growth stimuli for cell cycle progression and cell proliferation (17). They control the G1-to-S phase transition, a critical checkpoint that controls cell entry into mitosis. Cyclin E exerts its actions by activating cyclin-dependent kinase 2 and cyclin D1 by activating cyclin-dependent kinase 4/6. Cyclin E is rate limiting for S-phase initiation (18). In normal cells, cyclin E expression is under strict regulation, but in many tumors including breast cancer, regulatory processes are disturbed and cyclin E is overexpressed (17).

BRCA1 tumors express cyclin E more often than do sporadic tumors (19). Also in BRCA2 tumors, cyclin E is more frequently positive, but less so than in BRCA1 tumors (19). Cyclin D1 expression in BRCA1 tumors is lower than in sporadic tumors; in BRCA2 tumors, both lower and higher cyclin D1 expression has been reported (20–22). Cyclin E and cyclin D1 expression among familial non-BRCA1/2 tumors has not been studied.

In this study, we analyze cyclin E and cyclin D1 expression in a series of BRCA1-positive, BRCA2-positive, familial non-BRCA1/2, and sporadic breast cancers to evaluate their role in familial breast cancer.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Patients. Cyclin E and cyclin D1 expression was analyzed in breast tumors from a series of 798 familial BRCA1/2-negative, 53 BRCA1-positive, 58 BRCA2-positive, and 439 sporadic breast cancer patients (1,348 patients). Familial breast cancer patients were collected by a systematic screening at the Department of Oncology, Helsinki University Central Hospital (23), or were ascertained through genetic counseling at the Department of Clinical Genetics. Of the familial patients, 456 had stronger family history (at least three first- or second-degree relatives with breast or ovarian cancer, including the proband) and 342 patients had two affected first-degree relatives (including the proband). The genealogies were confirmed through population registries and cancer diagnosis through the Finnish Cancer Registry. All familial patients with stronger family history and 84% of patients from families with two affected cases have been screened and excluded for BRCA1 and BRCA2 mutations (1, 24). Unselected patients were collected at the Department of Oncology, Helsinki University Central Hospital, between 1997 to 1998 (25) and 2000 (26). The collected series had 884 unselected patients (79% of all consecutive, newly diagnosed breast cancer cases during the collection periods). Patients with family history for breast cancer are included in the familial series described above, leaving 439 sporadic breast cancer patients (patients with noninvasive cancer were excluded).

Patient characteristics are shown in Table 1 . Information on tumor histology, grade, size, nodal status, distant metastases, and ER and PR status were obtained from pathology reports (6). A breast cancer pathologist (P.H.) re-reviewed all tumors for tumor histology and grade. Grading was done according to Scarff-Bloom-Richardson modified by Elston and Ellis. HER2 protein expression on tissue microarrays was analyzed by immunohistochemical staining and gene amplification with chromogenic in situ hybridization (27, 28), and p53 protein expression by immunohistochemical expression, as previously described (29). The tissue microarrays were stained with a Ki-67 antibody (DakoCytomation) to evaluate Ki-67 protein expression (30). Tumors with Ki-67 expression above mean were considered as Ki-67 positive.


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  		Table 1. Tumor characteristics in the different patient groups

 
Tissue microarray construction. Paraffin blocks of the primary tumors were collected. The H&E-stained sections of the blocks were studied, and from the most representative tumor area four cores (diameter 0,6 µm) were punched and included in the tissue microarrays (two cores from BRCA1 and BRCA2 tumors). Subsequently, 3- to 4-µm-thick sections were cut from the array blocks and transferred to glass slides (6).

Immunohistochemistry. After deparaffinization in xylene and hydration in graded alcohols, all immunostainings were done in an automated immunostainer (Ventana Medical Systems, Inc.) with a diaminobenzidine kit (Ventana) to ensure standardized performance. Antigen retrieval was done with the iView-kit. Cyclin E (BD PharMingen) and cyclin D1 (Novocastra) were diluted 1:20. One investigator (Ki.A.) analyzed the tissue microarray slides. An experienced breast cancer pathologist (R-M.A.) advised on and controlled the scoring. The cyclin E– and cyclin D1–positive cells were counted in one high-power field (40x objective) in each of the four cores on tissue microarray. Only unequivocal positive nuclear staining was accepted as a positive reaction. A minimum of 200 cells were counted in each tumor. The result was the percentage of all positive cells from the entire number of breast cancer cells counted from the four biopsies. Cyclin E and cyclin D1 results were obtained from 88% of all tumors. Cyclin E result was missing from 161 (12%) tumors and cyclin D1 result from 168 (12%) tumors, due to lack of tumor on tissue microarray. The mean value of positively stained cells was 6.8% (range, 0-68%) for cyclin E and 9.1% (range, 0-81%) for cyclin D1. Tumors with expression above mean expression of all tumors (6.8% for cyclin E and 9.1% for cyclin D1) were considered as positive (high-expression tumors) and those below mean expression as negative (low-expression tumors).

Statistics. Statistical analyses were made with SPSS for Windows v12.0.1 (SPSS, Inc.). Due to multiple variables tested, the significance limit was set at 0.01. Cyclin E and cyclin D1 were dichotomized at mean value and differences in cyclin expression among different patient groups were determined by {chi}2 test. Logistic regression analysis (backward stepwise logistic regression, 99%) with cyclin E and cyclin D1 as continuous variables was used in multivariate analysis. Odds ratios (OR) for prevalence of combined immunotypes among groups were calculated by {chi}2 test.

Ethics. This study was done with informed consent from the patients as well as permissions from the Ethics Committee of the Helsinki University Central Hospital and the Ministry of Social Affairs and Health in Finland.


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
High cyclin E and low cyclin D1 expression was more common among BRCA1 than among familial non-BRCA1/2 or sporadic tumors. The frequency of BRCA1 tumors with high cyclin E expression (>6.8%) was 88%. In univariate analysis, this was significantly higher than cyclin E expression of familial non-BRCA1/2 (P < 0.00005) or sporadic (P < 0.00005) tumors (Table 2 ). Cyclin D1 expression was low (<9.1%) in 84% of BRCA1 tumors, which in univariate analysis was significantly more than among familial non-BRCA1/2 (P < 0.00005) or sporadic (P < 0.00005) tumors. Other factors differentiating BRCA1 tumors from familial non-BRCA1/2 as well as sporadic tumors in univariate analysis were high tumor grade; younger age at diagnosis; higher frequency of ER-, PR-, and HER2-negative and p53- and Ki-67–positive tumors; and higher frequency of tumors of medullary histology (Table 3 ). BRCA1 tumors also had more frequently negative nodal status than sporadic cases. In multivariate analysis, considering all the factors that are significant in univariate analysis, the differentiating factors between BRCA1 tumors and familial non-BRCA1/2 tumors were high cyclin E expression, low cyclin D1 expression, HER2 and ER negativity, and younger age at diagnosis (Table 4 ). Differentiating factors between BRCA1 and sporadic tumors were ER and HER2 negativity and younger age at diagnosis. Neither high cyclin E nor low cyclin D1 expression, however, was significant in multivariate analysis (Table 4).


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  		Table 2. Cyclin E and cyclin D1 expression in the different patient groups

 

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  		Table 3. Association of clinicopathologic features with tumors from the different patient groups in univariate analysis

 

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  		Table 4. Multivariate analysis of tumor features differentiating the patient groups

 
High cyclin E expression was more common among BRCA2 tumors than among familial non-BRCA1/2 tumors, and cyclin D1 expression among BRCA2 tumors than among familial non-BRCA1/2 or sporadic tumors. Of BRCA2 tumors, 58% had high cyclin E expression. The frequency of high cyclin E expression among BRCA2 tumors was higher than among familial non-BRCA1/2 tumors (P = 0.01), but only slightly higher than among sporadic tumors (P = 0.66; Table 2). The frequency of low cyclin D1 expression among BRCA2 tumors was 69%. It was significantly more often than among familial non-BRCA1/2 (P = 0.002) or sporadic (P = 0.009) tumors (Table 2). Other factors differentiating BRCA2 tumors from familial non-BRCA1/2 and sporadic tumors in univariate analysis were higher frequency of ER-, PR-, and HER2-negative tumors and younger age at diagnosis (Table 3). BRCA2 tumors were also more frequently N, M, and Ki-67 positive than were familial non-BRCA1/2 tumors and were more often of lobular histology than were sporadic tumors. In multivariate analysis, the independent factors differentiating BRCA2 tumors from familial non-BRCA1/2 tumors were high cyclin E and low cyclin D1 expression, HER2 negativity, younger age at diagnosis, and negative nodal status (Table 4); however, in comparison with sporadic tumors, only younger age at diagnosis and PR and HER2 negativity remained as independent factors (Table 4).

Cyclin E and cyclin D1 expression helped to differentiate BRCA mutation–positive from BRCA mutation–negative familial patients. High cyclin E expression, low cyclin D1 expression, younger age at diagnosis, and ER and HER2 negativity were the independent factors characterizing BRCA1 tumors compared with familial non-BRCA1/2 tumors in multivariate analysis. Prevalence of combined phenotypes defined by these factors was further compared between mutation-positive and familial mutation–negative tumors to evaluate the predictive value of these markers for BRCA mutation. Including both high cyclin E and low cyclin D1 expression increased the OR of BRCA1 mutation to 27.82, and high cyclin E to 28.85, as compared with OR 19.12 for traditional markers ER, HER2, and age at diagnosis alone (Table 5 ). Altogether, 62% of BRCA1 tumors had an ER–/HER2–/cyclin Ehigh phenotype and were diagnosed at age <50 years, and 55% had also low cyclin D1 expression. These factors predict also BRCA2 mutation and increase the OR for both BRCA1/2 mutations [OR, 10.80; 95% confidence interval (95% CI), 4.91-23.74] although not as substantially as for BRCA1 mutations.


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  		Table 5. Prevalence of combined immunotypes by ER, HER2, age at diagnosis, and cyclin E and cyclin D1 expression in BRCA1 tumors compared with BRCA1 mutation–negative familial (BRCA2 and non-BRCA1/2) familial tumors

 
Cyclin E expression differentiated familial non-BRCA1/2 tumors from both BRCA1/2-positive and sporadic tumors, and cyclin D1 expression from BRCA1/2-positive tumors. Among familial non-BRCA1/2 tumors, the frequency of high cyclin E expression was 38%, and low cyclin D1 expression 45%. As indicated above, in univariate analysis, the frequency of high cyclin E expression was significantly lower than among BRCA1, BRCA2, or sporadic tumors. The frequency of low cyclin D1 expression was significantly lower than among BRCA1 or BRCA2 tumors, and somewhat but not significantly lower than among sporadic tumors (Table 2). In univariate analysis, familial non-BRCA1/2 tumors were significantly more often Ki-67, N, and M negative than sporadic tumors (Table 3). In multivariate analysis, the independent factors differentiating familial non-BRCA1/2 from sporadic tumors were lower frequency of cyclin E–positive tumors and tumors with negative nodal status (Table 4). Cyclin E and cyclin D1 expression among families with two affected cases were similar as among sporadic tumors (Table 2).

To clarify the differences of expression in different groups, the percentages of cyclin E–positive, cyclin D1–negative, and cyclin E–positive/cyclin D1–negative tumors among BRCA1, BRCA2, familial non-BRCA1/2, and sporadic tumors are shown in Fig. 1 .


Figure 1
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  		Fig. 1. The percentage of cyclin E–positive, cyclin D1–negative, and cyclin E–positive/cyclin D1–negative tumors among familial non-BRCA1/2, BRCA1, BRCA2, and sporadic tumors. *, significantly different from the non-BRCA1/2 group.

 

   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
In this study, we have addressed the tumor phenotype of familial non-BRCA1/2 breast cancers and, specifically, the cyclin E and cyclin D1 expression, which has not been studied earlier, as well as compared these tumors with BRCA1/2-positive and sporadic cancers.

The majority of BRCA1 tumors in our study had high cyclin E (88%) and low cyclin D1 (84%) expression in concordance with previous immunohistochemical studies (20–22) and studies showing that high cyclin E expression characterizes the basal-like breast cancer subtype, the most frequent cancer type in BRCA1 mutation carriers (7, 8, 13). Indeed, high cyclin E and low cyclin D1 expression strongly predicted BRCA1 mutation when comparing BRCA1 tumors with familial non-BRCA1/2 cases in multivariate analysis. However, the only independent factors between BRCA1 and sporadic tumors were ER, age at diagnosis, and HER2. Similarly, high cyclin E expression and low cyclin D1 expression were independent predictors of a BRCA2 mutation in multivariate analysis when compared with familial non-BRCA1/2 tumors, but did not differentiate BRCA2 tumors from sporadic ones. To our knowledge, this has not been reported earlier and these data suggest a novel marker for predicting both BRCA1 and BRCA2 mutations among familial breast cancer cases. Because patients are usually referred to genetic counseling and testing based on their family history of cancer, identifying biological characteristics that predict BRCA1 and/or BRCA2 mutation among breast cancer families is also of high clinical importance.

The most important novel finding was that familial BRCA1/2 mutation–negative tumors with strong family history for breast and/or ovarian cancer differed significantly not only from BRCA1 and BRCA2 tumors but also from sporadic breast tumors by having significantly less frequently high cyclin E expression. Conversely, these tumors showed low cyclin D1 expression less frequently than BRCA1- or BRCA2-associated tumors. Cyclin E and cyclin D1 were independent factors characterizing familial non-BRCA1/2 tumors also in multivariate analysis. Cyclin E and cyclin D1 expression reflect crucial events in cell cycle control and tumorigenesis. Similarities in the cyclin E and cyclin D1 expression patterns among BRCA1 and BRCA2 tumors probably reflect the similarities in the functional roles of these two tumor suppressor genes in DNA repair, transcriptional regulation in response to DNA damage, and breast cancer predisposition (reviewed in ref. 31). BRCA1 also seems to have a direct role in cell cycle control by regulating the G2-M damage-induced checkpoint (32) and contributing to the control of p21 expression (33). The significantly different expression of cyclin E and cyclin D1 among familial non-BRCA1/2 tumors compared with both BRCA-associated and sporadic tumors, however, indicate that at least part of this group has unique biological characteristics and a genetic background that distinguishes them from BRCA1/2 and sporadic tumors. These differences in cyclin E and cyclin D1 expression are opposite to cyclin expression in BRCA mutation carriers. This indicates that whatever genetic change may lie behind these characteristics, it does not seem to involve the BRCA1 or BRCA2 pathway.

In conclusion, this study shows that cyclin E and cyclin D1 expression distinguishes familial non-BRCA1/2 tumors from both sporadic and BRCA1- and BRCA2-associated tumors and may reflect the different predisposition and pathogenesis in these groups.


   Acknowledgments
 
We thank Göran Landberg for his comments, Nina Puolakka for help with the study material, Majlis Book for technical assistance, and all the families that participated in our study.


   Footnotes
 
Grant support: Helsinki University Central Hospital Research Fund, Academy of Finland (110663), Finnish Cancer Society, and the Finnish Medical Foundation (Finska Läkaresällskapet).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 9/ 5/07; revised 12/ 2/07; accepted 12/15/07.


   References
Top
 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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