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Clinical Cancer Research 13, 46, January 1, 2007. doi: 10.1158/1078-0432.CCR-06-1490
© 2007 American Association for Cancer Research
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Human Cancer Biology

Radiation Effects on Development of HER2-Positive Breast Carcinomas

Fabio Castiglioni1, Monica Terenziani3, Maria Luisa Carcangiu4, Raffaella Miliano1, Piera Aiello1, Lorenzo Bertola1, Tiziana Triulzi1, Patrizia Gasparini2, Tiziana Camerini5, Gabriella Sozzi2, Franca Fossati-Bellani3, Sylvie Ménard1 and Elda Tagliabue1

Authors' Affiliations: 1 Molecular Targeting Unit and 2 Molecular Cytogenetics Unit, Department of Experimental Oncology, and 3 Pediatric Unit, 4 Pathology Unit, and 5 Scientific Board Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, "Istituto Nazionale dei Tumori", Milan, Italy

Requests for reprints: Sylvie Ménard, Molecular Targeting Unit, Department of Experimental Oncology, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy. Phone: 39-02-23902571; Fax: 39-02-23903073; E-mail sylvie.menard{at}istitutotumori.mi.it.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: Neither hormone-related nor genetics risk factors have been associated with the development of highly proliferative HER2-positive breast carcinomas. Because the majority of HER2-positive tumors present the amplification of the oncogene, we asked whether genomic instability triggered by irradiation might be involved in the induction of HER2-overexpressing breast carcinomas.

Experimental Design: Sixty-six infiltrating breast carcinomas from patients treated with radiation therapy for Hodgkin's lymphoma or other pediatric solid tumors and a control series of 61 consecutive sporadic breast tumors were analyzed by immunohistochemistry for HER2 expression with HercepTest. A panel of antibodies against estrogen receptor, progesterone receptor, c-kit, cytokeratin 5/6, p53, and ki67 antigen was also used to identify differentiation subsets and molecular characteristics of the analyzed breast carcinomas.

Results: Although no differences between the two tumor series were found with respect to HER2 expression scored 2+ and 3+, the percentage of 3+ HER2-positive tumors was significantly higher in patients irradiated during breast maturation compared with patients irradiated after breast maturation (35.3% versus 12.5%, P = 0.046). In the latter group, 52.5% of the breast carcinomas showed basal-like differentiation (estrogen receptor, progesterone receptor, and HER2 negative) versus only 5.9% in the group irradiated during breast development (P < 0.0001). Analysis adjusted for age confirmed the significant increase in basal-like tumor development in patients irradiated within 4 years of menarche, but also showed that the differences between patients irradiated before and after puberty in HER2 3+ tumor frequencies are due to age-related differences in HER2 3+ tumor onset.

Conclusion: Together, our data indicate that the development of HER2-positive tumors correlates with timing rather than type of carcinogenic hits and provide clear evidence that radiation is a risk factor for breast carcinomas showing basal-like differentiation.

Breast cancer is not a single disease but a group of different tumor subtypes presenting peculiar molecular characteristics (1). Different molecular analyses of gene expression profiles have identified at least four breast carcinoma subtypes: HER2-overexpressing, luminal, basal, and normal-like tumors. Amplification of the HER2 oncogene and related genetic elements in chromosome 17 causes a marked increase (up to 100-fold) in the expression of HER2 on the surface of breast cancer cells. Besides a distinct molecular signature, HER2-positive breast carcinomas also have distinctive clinical features. Several studies have shown that overexpression of HER2 is an adverse prognostic factor associated with poorly differentiated, highly proliferative tumors (2).

The various breast cancer risk factors identified to date, such as parity, age at menarche and at menopause, pregnancy, hormone replacement therapy, and others, such as mutations of BRCA1 and BRCA2, have been associated only with the development of HER2-negative tumors (3–5). The literature shows that women irradiated for Hodgkin's disease when <30 years of age have a higher relative risk of developing breast cancer (6–11). Moreover, studies of cancer risk in groups exposed to unusually high radiation levels, including survivors of the Hiroshima atomic bomb blast, showed an increased tendency of women to develop breast cancer (12–14). Ionizing radiation is known to induce DNA damage or aberrant recombination of chromosomes during cellular mitosis. For example, radiation can induce p53 gene alterations in human normal breast cells, and injection of these cells into nude mice leads to tumor development in 100% of cases (15). Because the majority of HER2-positive tumors present amplification of the oncogene, we asked whether genomic instability triggered by irradiation might be involved in the induction of HER2-overexpressing breast carcinomas. We describe here our comparison of the frequency of HER2-positive tumors in previously irradiated breast tumor patients versus nonpreviously irradiated, sporadic breast tumor patients. A panel of antibodies against estrogen receptor (ER), progesterone receptor (PgR), c-kit, cytokeratin 5/6, p53, and ki67 antigen was also used to identify differentiation subsets and molecular characteristics of the breast carcinomas analyzed.


   Materials and Methods
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 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Patients. Samples of breast carcinoma that arose after radiation therapy were obtained from 77 patients affected by Hodgkin's lymphoma (88%), Wilms' tumor (5%), Ewing sarcoma (4%), or non–Hodgkin's lymphoma (3%) between 10 and 20 years (36 cases), 21 and 40 years (36 cases) and >41 years (5 cases). All patients had received radiation in the breast area (mean dose, 36 Gy; range, 15.6-66 Gy) combined in 62% of the cases with chemotherapies such as MOPP (36%), ABVD (17%), both schedules (17%), or other drug combinations (e.g., ABV, APVD, Adriamycin + vincristine, and others; 30%). Patients developed a primary breast carcinoma after a median latency of 17 years (range, 9-31 years), and tumors were in situ (13%) or infiltrating (87%), and only the latter (66 tumors) were included in the analyses. Samples of sporadic breast carcinoma were obtained from 61 patients who were consecutively surgically treated at the National Cancer Institute of Milan from March to April 2005. Table 1 lists the clinical characteristics of both patient series. A case-control series matched by age was also analyzed. Specifically, two consecutive controls were matched to each radiation-preceded breast carcinoma case; percentage of node infiltration and grade 3 and expression of hormone receptors and HER2 were considered.


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  		Table 1. Clinicopathologic features of infiltrating breast carcinomas

 
Institutional approval from our Ethics Committee was obtained for the conduct of the study. Patients had agreed to the use of samples from their tumors for future investigation, although they did not provide written permission for the present study, which was done many years after the initial diagnosis.

Immunohistochemistry. Immunohistochemical staining was carried out on formalin-fixed, paraffin-embedded tissue using heat-induced epitope retrieval in 10 mmol/L citrate buffer, pH 6.0, testing for the following markers: accumulation of p53 using monoclonal antibody DO7 (DAKO, Glostrup, Denmark); tumor proliferation using MIB-1 monoclonal antibody (DAKO); ER and PgR expression using 1D5 and PgR636 monoclonal antibodies (DAKO), respectively; c-kit and cytokeratins 5/6 using polyclonal rabbit anti-human CD117–c-kit (DAKO) and D5/16B4 monoclonal antibody (Zimed Laboratories Inc.), respectively; and HER2 oncoprotein overexpression using HercepTest (DAKO). The immunoreaction was developed using the streptavidin-biotin-peroxidase technique, followed by counterstaining with Carazzi hematoxylin. Sections were scored p53-, ER-, PgR-, and MIB-1–positive when {gtrsim}10% of the tumor cells were labeled. HER2 was evaluated as 0, 1+, 2+, or 3+ according to the HercepTest score and considered positive when 2+ and 3+ membrane labeling was observed. c-kit and cytokeratins 5/6 were considered positive when more than 5% of the tumor cells were labeled.

Fluorescence in situ hybridization. All HER2 2+ and 3+ irradiation-preceded cases were evaluated by fluorescence in situ hybridization using the PathVysion HER-2 DNA Probe kit (Vysis, Downers Grove, IL) according to the manufacturer's recommendations. The kit contains two commercially labeled probes: LSI HER-2 DNA SpectrumOrange probe of 190 kb specific for the gene HER-2 (17q11.2-q12) and CEP 17 DNA SpectrumGreen probe specific for the DNA {alpha}-satellite sequence of chromosome 17 centromere. Briefly, the 2-µm paraffin sections were placed in Hybrite (Vysis) at 56°C for 1 h, washed in a xylene series, rehydrated (100% and 96% ethyl alcohol) and placed in TE buffer (5 mmol/L Tris-HCl and 1 mmol/L EDTA, pH = 7.0) for 15 min at 96°C. After pepsin treatment (0.01 N HCl + 0.4% pepsin) done in Hybrite (Vysis) at 37°C for 6 min followed by dehydration in 95% ethyl alcohol for 3 min, samples were denatured in Hybrite (Vysis) at 85°C for 1 min, hybridized with probes overnight at 37°C, and washed in 2x SSC/0.3% NP40 at 73°C for 2 min. Samples were stained with 4',6-diamidino-2-phenylindole, coverslipped, and analyzed with a Zeiss Axioscop 2 microscope (Carl Zeiss, Milan, Italy). Images were acquired using FISHVIEW (ver 4.0, ASI, Vista, CA).

Statistical analysis. Univariate analyses and logistic regression models were done with the STATA statistical data program (StataCorp LP, College Station, TX). Differences in frequencies of clinicopathologic or biological parameters were analyzed using a {chi}2 test. Differences were considered significant at P < 0.05. Missing data were excluded during analyses and not considered in calculating parameter frequencies.


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Paraffin-embedded sections of 66 infiltrating breast carcinomas, obtained from patients previously treated for Hodgkin's lymphoma or other solid pediatric tumors, and of 61 consecutive sporadic infiltrating breast carcinomas were tested by immunohistochemistry for the expression of HER2 and other biological markers, such as ER, PgR, p53, MIB-1, CD117 (c-kit), and cytokeratin 5/6. Fluorescence in situ hybridization analysis of HER2-positive radiation-preceded breast carcinomas revealed amplification of the HER2 gene in 9 of 11 HER2 3+ tumors and in only 1 of 5 (20%) HER2 2+ cases (data not shown), consistent with results previously obtained on sporadic breast carcinomas examined in our institute (16), indicating that for irradiated patients HER2 3+, immunohistochemistry results also reflect mainly HER2 gene amplification.

Analyses of pathologic features showed no significant differences in tumor size and lymph node infiltration between breast carcinomas that developed in previously irradiated patients and the consecutive series except for grade 3 tumors, which were more frequent in irradiated patients (Table 1). When HER2 was considered, no differences were observed between the two series of tumors, nor was there any significant difference in the percentage of MIB-1–positive breast carcinomas (Table 2 ). By contrast, the percentage of estrogen- and progesterone-positive tumors was significantly lower in breast carcinomas arising after irradiation compared with the consecutive series (ER, 50% versus 72.9%; and PgR, 31.2% versus 58.3%; P = 0.009 and P = 0.002, respectively). Moreover, a significant increase in p53 and cytokeratin 5/6 immunohistochemical reactivity was observed in primary breast cancers of previously irradiated patients compared with the consecutive series (35.8% versus 10.2%, P = 0.001; and 45.4% versus 17.3%, P = 0.003, respectively; Table 2). Due to the significantly younger median age of radiation-preceded breast carcinomas compared with control series, a logistic regression model including age was constructed using pathobiological features that differed significantly between the two series. Only p53 and cytokeratin 5/6 were found to be significant predictors after adjustment for age (P = 0.001 and P = 0.037, respectively), indicating that radiation therapy increases the odds ratio for development of breast carcinomas expressing cytokeratin 5/6 and/or presenting p53 accumulation. By contrast, hormone receptor expression lost significance (Table 3 ). Because a 3-fold increased risk of breast cancer development has been reported for women receiving >40 Gy compared with women receiving ≤40 Gy (17), HER2 expression was also analyzed according to radiation dose; HER2 expression did not change significantly (data not shown), although a slight increase in HER2-positive tumors scored 3+ was found in women irradiated with more than 40 Gy (3 of 8 versus 7 of 46 in patients irradiated with ≤40 Gy). The use of chemotherapy did not modify the frequency of HER2-positive breast carcinomas in irradiated patients compared with tumors arising in women treated with radiation only or compared with sporadic carcinomas. Indeed, HER2-positive tumors (2+ and 3+ combined) were found in 11 of 46 patients treated with chemotherapy plus irradiation, 6 of 20 treated only with irradiation, and 16 of 57 sporadic breast carcinoma patients. Based on studies indicating that the highest risk of breast cancer in irradiated women corresponds to puberty (6, 18) when breast tissue is most active and, thus, most susceptible to carcinogenic effects of radiation, the frequencies of HER2-positive tumors were analyzed in the breast carcinoma series with respect to the stage of breast tissue maturation at the time of radiation. It is well known that breast tissue develops during puberty, particularly in the 2 years before and 4 years after menarche when breast wool mounts increase by sexual hormone stimulation (8). Two groups of breast carcinoma patients were considered: (a) women who received irradiation before or within 4 years from menarche; and (b) women treated with radiation after 4 years from menarche. The percentage of HER2-positive tumors, considering only those scored 3+, was significantly higher in patients irradiated during breast maturation compared with patients irradiated after breast maturation (35.3% versus 12.5%, P = 0.046; Table 4 ). Moreover, the percentage of tumors expressing hormone receptors (ER and PgR) was significantly higher in patients irradiated during versus after breast maturation (71.4% versus 39.5%, P = 0.017; and 71.4% versus 34.9%, P = 0.007, respectively), whereas the frequency of p53-positive tumors was lower in patients irradiated during breast maturation as compared with patients irradiated after breast maturation (16.6% versus 45.7%, P = 0.037). No differences between the two subgroups were observed for MIB-1, c-kit, or cytokeratin 5/6 expression. Comparison of tumors from each subgroup to those of the sporadic consecutive series revealed no significant differences in the expression of biological markers for tumors of patients treated with radiation during breast development, whereas tumors of patients treated when breast tissue had already matured showed a significantly lower frequency of ER (39.5% versus 72.9%, P = 0.0007) and PgR (34.9% versus 58.3%, P = 0.018) expression. In this latter group, the percentage of p53- and cytokeratin 5/6-positive tumors was significantly higher compared with the sporadic consecutive series (45.7% versus 10.2%, P < 0.0001; and 53.3% versus 17.3%, P = 0.0006, respectively).


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  		Table 2. Biological characteristics of infiltrating breast carcinomas

 

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  		Table 3. Logistic regression model of radiation-preceded breast carcinomas compared with sporadic consecutive tumors

 

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  		Table 4. Biological characteristics of radiation-preceded breast carcinomas according to mammary gland maturation level at time of irradiation

 
An immunohistochemical definition of breast carcinoma subtypes has been formulated based on the association of HER2 expression with the HER2 differentiation subtype; ER and PgR expression with the luminal differentiation subtype; and triple-negative cases with the basal-like breast tumors (19). These categories were defined as (a) HER2 for 3+ HER2-positive tumors; (b) luminal for ER- or PgR-positive and HER2 other than 3+ tumors; and (c) basal-like for ER- and PgR-negative and HER2 other than 3+ tumors. Because our results above indicate age-dependent HER2 levels in breast carcinoma and because the median age of patients treated during breast tissue maturation was significantly younger than patients treated after breast maturation (32 versus 45 years; P < 0.0001), we considered two case-control series, each matched by age with radiation-preceded tumors. By this classification, the frequency of HER2-positive carcinomas was higher in patients irradiated during breast maturation compared with that in women irradiated after breast maturation (35.3% versus 12.5%, P = 0.046). The incidence of HER2-positive tumors was also higher in control series matched for age with patients treated before puberty (32.3%), compared with control series matched for age with patients treated after puberty (21.2%). The percentage of tumors classified as luminal was significantly lower in patients irradiated after breast maturation (P = 0.0007) compared with the properly matched series. Consequently, in the latter group, basal-like primary breast carcinomas represented 52.5% versus only 5.9% and 11.3% of tumors in the groups irradiated during breast development and nonirradiated age matched, respectively (P < 0.0001). Furthermore, the frequencies of the three subtypes differed significantly (P = 0.0001) only when simultaneously analyzed in patients treated after breast tissue maturation and each corresponding age-matched control series (Table 5 ).


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  		Table 5. Frequency of immunohistochemically defined breast tumor subtypes

 

   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
The present study suggests that radiation administered during breast maturation can be a risk factor for the development of HER2-overexpressing breast carcinomas presenting amplification of HER2 oncogene. In fact, the frequency of HER2 3+ tumors was significantly higher in women irradiated for Hodgkin's lymphoma or other pediatric solid tumors within 4 years of menarche compared with patients irradiated after puberty. These findings might rest on the ability of ionizing radiation to induce direct DNA damage, leading to gene amplification, or to affect genes involved in DNA repair, which are particularly active when breast ducts and lobules are elongating. The increased frequency of HER2 3+ tumors in women who received >40 Gy compared with those treated with a radiation dose ≤40 Gy indicates that DNA injury related to HER2 amplification also depends on the dose of radiation received. By contrast, chemotherapy did not seem to have any genotoxic effect on the HER2 gene because no variations were observed in the frequencies of HER2-positive tumors in patients who received or did not receive chemotherapy before and after irradiation. However, data obtained in logistic regression models as well as in age-matched control series are consistent with previous reports that HER2-positive tumors present an increased incidence in young patients (20, 21) and strongly support the notion that HER2 levels are more correlated to timing than to type of carcinogen. Thus, any carcinogen that induces DNA instability might increase the frequency of tumors displaying HER2 gene amplification, if introduced during breast tissue maturation.

On the other hand, the significantly higher percentage of p53- or cytokeratin 5/6–positive tumors in irradiated women compared with those with sporadic tumors, even after adjustment for age, provides strong evidence that radiation-induced gene instability can affect the molecular characteristics of breast carcinomas, and that radiotherapy administered after breast development is a risk factor for undifferentiated primary breast carcinomas showing basal-like differentiation.

Recent studies have shown that the mammary gland develops through progressive differentiation of a primitive stem cell, which produces the cellular components found in the adult mammary gland (22, 23). Although stem cells themselves divide slowly, progenitor cells derived from them are highly proliferative (24) and can differentiate into lineages comprising adult breasts. Because proliferation potential decreases irreversibly with differentiation, progenitor cells are likely candidates for accumulating the multiple mutations involved in carcinogenesis. These cells are exposed to damaging agents for long periods and can divide many times, enabling the propagation of the mutations induced by a genotoxic agent. Thus, upon radiation-induced damage, early progenitor cells proliferating in the mammary gland during puberty can become "cancer stem cells" for HER2-positive tumors. Furthermore, because tumors that arose in women irradiated for Hodgkin's disease within 4 years of menarche were preferentially of two different subtypes, i.e., luminal or HER2, it is possible that cancer stem cells represent an amplifying population of progenitors at different levels of differentiation, which can also give rise to differentiated tumors expressing hormone receptor, as recently proposed by Wicha et al. (25). Consistent with the hypothesis that the mammary gland during puberty contains proliferating precursors at different levels of differentiation, Zeps et al. showed that increased levels of estrogen in pubescent mice generate both ER+ and ER– transiently amplifying progenitor cells (26, 27). Indeed, ER+ progenitors proliferate in response to increased estrogen and can also produce paracrine factors that influence the proliferation and/or differentiation of the adjacent ER– cell population. The finding that primary breast carcinomas in women irradiated upon breast maturation were of the basal subtype in more than 50% of cases again supports the notion that breast carcinomas arise from mutations in precursors cells. Indeed, basal-like tumors present molecular characteristics peculiar to early progenitors cells, the only progenitor cells present in the adult mammary gland. Consistent with a stem cell and/or progenitor cancer model, markers expressed in mouse mammary stem cells were shown to be similar to those of human basal breast carcinomas; whereas stem cell–derived colony-forming cell progeny was present in ER- and PgR-positive luminal tumors (28). Finally, the high percentage of sporadic tumors with hormone receptor–positive cells is consistent with breast transformation–related damage initiated at puberty, with lifestyle, and/or hormonal risk factors affecting breast carcinogenesis thereafter.

Together, our data suggest that radiation, like other carcinogenic agents, administered before puberty can be a risk factor in the development of HER2-positive breast carcinomas presenting HER2 gene amplification and show that genetic destabilization of even late precursor cells already committed to forming the mammary tree can lead to tumor initiation.


   Acknowledgments
 
We thank Daniela Silva for manuscript preparation and Dr. Attilio Cecchetto (University Hospital, University of Padua) and Dr. Alberto Bellomi (Ospedale Civile Carlo Poma, Mantova) for providing breast carcinoma samples.


   Footnotes
 
Grant support: Associazione Italiana per la Ricerca sul Cancro.

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 6/21/06; revised 9/15/06; accepted 10/19/06.


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