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© 2002 American Society for Clinical Oncology
Estrogen Receptor-Beta Expression in Hereditary Breast Cancer
Istituto Nazionale Tumori, *Fondazione Italia per la Ricerca sul Cancro, Institute of Molecular Oncology, Milan, Italy To the Editor:The recent article by Lakhani et al1 provides solid data in favor of a distinctive morphologic and immunohistochemical profile of breast cancers from patients carrying mutations in BRCA1 gene and confirms previous results2 indicating a significant role of estrogen receptor (ER), in association with histologic grade and patient age, in predicting BRCA1 status. Based on risk estimates, the Lakhani et al1 exemplify that a 30- to 34-year-old woman presenting with ER-negative, histologic grade 3 breast cancer would have a 27% probability of harboring a BRCA1 mutation compared with the 5% probability observed for a woman with ER-positive tumor. This level of risk of carrying a BRCA1 mutation would justify the need of expensive genetic testing to be extended to family members and specific preventive interventions.
Standard recommendations for breast and ovarian cancer surveillance include annual mammography, two to four times annually clinical breast examination, biannual transvaginal ultrasound, serum CA-125 screening, and monthly breast self-examination. In addition, the more harsh procedures of prophylactic bilateral mastectomy and oophorectomy are effective risk reducers, but acceptance by women is obviously low. A recent study by Scheuer et al3 points to the poor effectiveness of the prevention strategies and strongly suggests a reassessment of these recommendations. The third option, chemoprevention with tamoxifen, is still controversial and needs further discussion. In their study, based on data demonstrating that the majority of BRCA1-mutated tumors are ER-negative, Lakhani et al1 state that breast tumors arising in BRCA1 carriers will be relatively resistant to hormonal therapy and express doubt about the efficacy of hormonal chemoprevention. However, a recent retrospective case-control study by Narod et al4 for the Hereditary Breast Cancer Clinical Study Group showed a protective effect of tamoxifen in preventing contralateral tumors in breast cancer patients with mutations in BRCA1 and BRCA2 genes and demonstrated that this protective effect was independent of that of oophorectomy. Interestingly, tamoxifen seems to exert a greater benefit in BRCA1 than in BRCA2 mutation carriers, despite the prevalence in the former subset of an ER-negative phenotype5 (as defined by determining the classical ER- In an attempt to understand tamoxifen protective effect in BRCA1 mutation carriers and to further characterize hereditary breast tumors, we investigated whether hereditary breast cancers differ in the expression of the novel ER-ß subtype, involved in the modulation of the cellular response to estrogens and antiestrogens. The role of ER-ß in favoring the antagonistic effect of antiestrogens is supported by the association between protein expression and favorable outcome after tamoxifen treatment, recently demonstrated in an adjuvant setting,6 and the dominant regulatory role of ER-ß in estrogen signaling,7,8 which would potentiate the antagonistic effects of tamoxifen. In addition, we observed a two- to four-fold upregulation of ER-ß mRNA compared with controls after 24- to 48-hour treatment with 10-8M and 10-7M tamoxifen in the hormone-dependent T47D cell line (data not shown). We immunohistochemically evaluated ER-ß expression (using a polyclonal antibody developed by M. Younes6) in formalin-fixed, paraffin-embedded primary breast cancer specimens from 44 familial cases, including 28 mutation carriers (16 BRCA1 and 12 BRCA2) and 16 subjects negative to mutation testing (BRCA-X), and compared it with that of 90 nonfamilial breast cancer patients matched for age and year of initial diagnosis. ER-ß positivity (greater than 10% immunoreactive cells) was observed in 84% (37 of 44) of hereditary breast cancers compared with 69% (62 of 90) of nonfamilial tumors. In particular, positive staining for ER-ß was detectable in almost all (94%, or 15 of 16) BRCA1 tumors (BRCA1 v nonfamilial cancers, P = .06 by two-tailed Fisher’s exact test), in 75% (nine of 12) of BRCA2 tumors, and 81% (13 of 16) of BRCA-X cancers.
ER-ß has been described to act as a dominant negative regulator of ER- REFERENCES
1. Lakhani SR, van de Vijver MA, Jacquemier J, et al: The pathology of familial breast cancer: Predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 20: 2310-2318, 2002
2. Chang J, Hilsenbeck SG, Hwei Sng J, et al: Pathological features and BRCA1 mutation screening in premenopausal breast cancer patients. Clin Cancer Res 7: 1739-1742, 2001
3. Scheuer L, Kauff N, Robson M, et al: Otcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers. J Clin Oncol 20: 1260-1268, 2002 4. Narod SA, Brunet JS, Ghadirian P, et al: Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control study. Lancet 356: 1876-1881, 2000[CrossRef][Medline] 5. Loman N, Johannsson O, Bendhal P-O, et al: Steroid receptors in hereditary breast carcinomas associated with BRCA1 or BRCA2 breast cancer mutations or unknown susceptibility genes. Cancer: 83: 310-319, 1998[CrossRef][Medline] 6. Mann S, Laucirica R, Carlson N, et al: Estrogen receptor beta expression in invasive breast cancer. Human Pathol 32: 113-118, 2001[CrossRef][Medline] 7. Pettersson K, Delaunay F, Gustafsson JA: Estrogen receptor ß acts as a dominant regulator of estrogen signaling. Oncogene 19: 4970-4978, 2000[CrossRef][Medline]
8. Hall JM, McDonnell DP: The estrogen receptor ß-isoform (ERß) of the human estrogen receptor modulates ER 9. Fan S, Ma YX, Wang C, et al: Role of direct interaction in BRCA1 inhibition estrogen receptor activity. Oncogene 20: 77-87, 2001[CrossRef][Medline]
ResponseMemorial Sloan-Kettering Cancer Center, New York, NY In Reply:The letter to the editor by Daidone et al is intriguing and provides a possible biologic rationale for the use of hormonal therapy for breast cancer prevention in BRCA1 mutation carriers. In a recent report in the Journal of Clinical Oncology, we showed that a combination of intensive screening and "risk-reducing" surgeries led to the detection of early-stage breast and ovarian cancers in a series of 251 individuals with BRCA1 and BRCA2 mutations.1 Although these results were encouraging, they did not address the issue of chemoprevention in these patients. Other published studies examining this issue have yielded conflicting results. A case-control series by Narod et al2 showed tamoxifen lowered contralateral breast cancer risk in both BRCA1 and BRCA2 mutations carriers. However, King et al3 did not demonstrate a benefit for tamoxifen chemoprevention in BRCA1 carriers participating in the National Surgical Adjuvant Breast and Bowel Project P-1 trial. A prospective series by our group4 and a retrospective series by Rebbeck et al5 both recently reported a significant reduction in subsequent breast and BRCA-related gynecologic cancers after risk-reducing oophorectomy in BRCA1 and BRCA2 mutation carriers. However, neither of these series was powered to examine possible differences in risk-reduction between BRCA1 and BRCA2 mutation carriers. Studies such as those reported by Lakhani et al6 and Daidone et al will help to clarify the biologic mechanisms by which hormonal manipulation may alter breast cancer risk. These insights will provide the foundation for clinical trials of chemoprevention in women at highest hereditary risk for breast cancer. REFERENCES
1. Scheuer L, Kauff N, Robson M, et al: Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutations carriers. J Clin Oncol 20: 1260-1268, 2002 2. Narod SA, Brunet JS, Ghadirian P, et al: Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: A case-control study. Lancet 356: 1876-1881, 2000[CrossRef][Medline]
3. King MC, Wieand S, Hale K, et al: Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2. JAMA 286: 2251-2256, 2001 4. Kauff ND, Satagopan JM, Robson ME, et al: Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 346: 1610-1615, 2002 5. Rebbeck TR, Lynch HT, Neuhausen SL, et al: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346: 1616-1622
6. Lakhani SR, van de Vijver MJ, Jacquemer J, et al: The pathology of familial breast cancer: Predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 20: 2310-2318, 2002
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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subtype expression by ligand binding assay or immunohistochemistry). 
