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[Cancer Research 64, 5051-5053, August 1, 2004]
© 2004 American Association for Cancer Research

Advances in Brief

Increased Progesterone Receptor Expression in Benign Epithelium of BRCA1-Related Breast Cancers

Tari A. King1, Mary L. Gemignani1, Weiwei Li1, Dilip D. Giri2, Kathy S. Panageas3, Faina Bogomolniy1, Crispinita Arroyo1, Narciso Olvera1, Mark E. Robson4, Kenneth Offit4, Patrick I. Borgen1 and Jeff Boyd1,4

Departments of 1 Surgery, 2 Pathology, 3 Epidemiology and Biostatistics, and 4 Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
The study of pathologically normal breast epithelium of BRCA mutation carriers may yield insights into the early natural history of breast tumorigenesis. Hormone receptor expression was assessed in 24 cases of invasive breast cancer associated with a mutation in BRCA1 (n = 15) or BRCA2 (n = 9) and in 39 sporadic cases matched for patient age and tumor hormone receptor status. Expression of progesterone receptor was significantly (P = 0.0003) more common in normal breast epithelium adjacent to invasive breast carcinoma in BRCA1-linked cases compared with sporadic cases. The wild-type BRCA allele was retained in normal epithelium of all cases tested. We conclude that deregulation of progesterone receptor expression, as a result of BRCA1 haploinsufficiency, may represent an early event in BRCA1-linked breast tumorigenesis.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
An estimated 5–10% of breast cancers are associated with autosomal dominant genetic predisposition, and a substantial proportion of these are linked to BRCA1 or BRCA2 (reviewed in Ref. 1 ). The availability of genetic testing for BRCA mutation greatly increases the need for definition of the risks and benefits of various clinical interventions aimed at risk reduction. Options for persons determined to be at high risk for breast cancer as a result of BRCA mutation include surveillance, chemoprevention, and prophylactic mastectomy, but few prospective data exist to support the efficacy of these procedures. An increased understanding of the early natural history of breast tumorigenesis in BRCA heterozygotes with respect to hormone receptor expression is vital for a rational approach to the development of chemopreventive strategies for this population. Toward that end, an emerging body of data suggests that human cells heterozygous for a BRCA mutation display a phenotype consistent with BRCA haploinsufficiency, insofar as dermal fibroblasts and lymphocytes from BRCA heterozygotes display an enhanced sensitivity to ionizing radiation compared with cells from control individuals (2 , 3) , and in BRCA2 mutation carriers, biallelic inactivation of BRCA2 appears to be a late event in the development of pancreatic intraepithelial neoplasia (4) . The purpose of this study was to search for evidence of BRCA haploinsufficiency in pathologically normal breast epithelium of BRCA heterozygotes with breast cancer, focusing on hormone receptors as clinically relevant molecular markers of this phenomenon.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Twenty-four patients with deleterious germ-line mutations in BRCA1 (n = 15) or BRCA2 (n = 9) and a diagnosis of invasive breast carcinoma were identified through the Clinical Genetics Service of the Memorial Sloan-Kettering Cancer Center. These patients had previously provided informed consent for BRCA genetic testing, and this particular study was approved by the Institutional Review Board of the Memorial Sloan-Kettering Cancer Center. For each BRCA-linked breast cancer case, two additional cases of presumed sporadic invasive breast carcinoma were selected from a Department of Surgery breast cancer database; these cases were matched for age at diagnosis (within 3 years) and tumor hormone receptor status with the BRCA-linked cancers. Premenopausal patients were not matched for menstrual cycle phase. Corresponding tissues were obtained as fixed and paraffin-embedded specimens from Department of Pathology archives, tissue sections were prepared as appropriate for the various analyses (see below), relevant clinicopathological annotation was attached to each case, and the tissue samples were then anonymized. Adequate tissue specimens were not available for 9 sporadic breast cancer cases, leaving 39 available for analysis.

All cases were reviewed by two study pathologists to confirm the diagnosis of invasive breast carcinoma, to delineate regions of normal epithelium, preinvasive lesions, and cancer, and to score tumors for hormone receptor expression status for the purpose of matching sporadic cases with BRCA-linked cases. Hormone receptor status was scored as positive if ≥10% of tumor cells were immunopositive for ER (estrogen receptor) or PgR (progesterone receptor) expression as assessed by immunohistochemical staining; these are the standard criteria used by the Department of Pathology at this institution and are considered to accurately predict for a positive clinical response to endocrine therapy.

For immunohistochemical analyses, several representative tissue sections of 6-µm thickness containing invasive carcinoma and/or normal epithelium were prepared from paraffin blocks associated with each case and placed on silanized glass slides. The DAKO LSAB2 System, Peroxidase, was used in conjunction with the DAKO Autostainer Universal Staining System according to instructions supplied by the manufacturer. Briefly, slides were deparaffinized in xylenes and rehydrated in a graded series of ethanol/water rinses, and antigen retrieval was performed by heating slides in a steamer to 95°C–99°C in Target Retrieval Solution (DAKO) for 20 min. At room temperature, slides were then treated with 3% hydrogen peroxide for 10 min followed by primary antibody for 10 min. For ER, the monoclonal mouse antihuman clone 1D5 (DAKO) was used at a 1:50 dilution; for PgR, the monoclonal mouse antihuman clone PgR 636 (DAKO) was used at a dilution of 1:75. Visualization using the LSAB2 System is accomplished using a biotinylated link antibody, peroxidase-streptavidin, and 3,3'-diaminobenzidine as chromogen. Slides were counterstained with methyl green.

Hormone receptor expression in normal breast epithelium, as a percentage of cells displaying positive nuclear staining, was scored as a continuous variable and potential differences between the various groups were assessed using the Student’s t test. All reported P values were corrected for multiple testing using the step-down Bonferroni procedure of Holm (5) .

Microdissection of normal and tumor cells from tissue sections prepared from paraffin blocks was accomplished using a P.A.L.M. Laser Pressure Catapulting microdissection system (P.A.L.M. Mikrolaser Technologies). Quantitative allelotyping of DNA from microdissected cells was performed using a real-time multiplex allele-specific PCR procedure developed for the detection of specific frameshift mutations in BRCA1 (185delAG) and BRCA2 (6174delT), which were present in 54% of the BRCA heterozygotes analyzed. This procedure allows the precise quantitation of mutant versus normal alleles in a single DNA sample. Details of these procedures, including PCR primer and probe sequences, are available upon request.


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
The clinicopathological characteristics of BRCA-linked and sporadic breast cancer cases are summarized in Table 1Citation . The sporadic cases were selected to closely match the BRCA-linked group for patient age at diagnosis and tumor hormone receptor expression status. In addition, the two groups were very similar with respect to histological cell type and grade, tumor size, presence of vascular invasion, presence of lymph node metastases, and stage.


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  		Table 1 Clinicopathological characteristics of breast cancer cases

 
For each case, hormone receptor expression in normal breast epithelium was assessed in two regions from the breast specimen from two separate paraffin blocks, one containing both normal epithelium and tumor and the second containing only normal epithelium. These two regions of normal epithelium were labeled as "adjacent to tumor" and "at an unknown distance from tumor," respectively (Fig. 1)Citation . Expression of ER was not significantly different in normal breast epithelium from either region when comparing all BRCA-linked cases together to the sporadic cases (data not shown). When considering the BRCA1- and BRCA2-linked cases separately, there was a trend toward a higher proportion of cells expressing ER in both regions of normal epithelium in BRCA1-linked cases compared with either of the other two groups, but these differences did not reach statistical significance.



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  		Fig. 1. Representative photomicrograph demonstrating a region of normal breast epithelium displaying nuclear immunopositivity for PgR expression adjacent to invasive breast carcinoma (top) from a BRCA1 heterozygote.

 
Although the proportion of cells expressing PgR was higher in all BRCA-linked cases compared with sporadic cases in both areas of normal epithelium assessed, these differences were not statistically significant (data not shown). However, when considered separately, BRCA1-linked cases showed significantly higher PgR expression than sporadic cases in normal epithelium adjacent to tumor (P = 0.0003) and higher PgR expression of marginal significance at an unknown distance from tumor (P = 0.06; Table 2Citation ). Expression of PgR was also marginally significantly higher in BRCA1-linked cases compared with BRCA2-linked cases in normal epithelium at an unknown distance from tumor (P = 0.06) but not adjacent to tumor. Expression of PgR in BRCA2-linked tumors was not significantly different from that in sporadic tumors.


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  		Table 2 Mean hormone receptor expression in normal breast epithelium of BRCA-linked and sporadic breast cancer cases

 
To search for evidence of loss of the wild-type BRCA allele in normal breast epithelium that may correlate with aberrant hormone receptor expression, a real-time PCR procedure was developed to quantitate the ratio of mutant to wild-type BRCA alleles in DNA from microdissected normal breast epithelium obtained from patients with the 185delAG BRCA1 mutation (n = 6) or the 6174delT BRCA2 mutation (n = 2). In these eight cases that were extensively analyzed, there was no evidence for allelic loss in normal epithelium either adjacent to or at an unknown distance from tumor, although loss of the wild-type allele was readily demonstrated in multiple cases of BRCA1-linked and BRCA2-linked invasive cancers (data not shown).


   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
These data indicate that PgR is aberrantly expressed in pathologically normal breast epithelium of BRCA1 mutation carriers with breast cancer. No evidence was found for statistically significant alterations in ER expression or cell proliferation in normal breast epithelium of BRCA mutation carriers compared with that of sporadic breast cancer patients. Retention of the wild-type BRCA1 allele in normal breast epithelium of these cases suggests that PgR deregulation is occurring in association with BRCA1 haploinsufficiency. These findings have several implications related to the early natural history of breast tumorigenesis in the BRCA1 population.

Although the literature on hormone receptor expression in normal breast epithelium is limited, available evidence indicates that ER expression is present in nearly all terminal duct lobular units but in only a small proportion of luminal epithelial cells in these units. In premenopausal women, the proportion of ER-positive cells ranges from 4 to 20%, depending on the phase of the menstrual cycle; these cells are distributed singly and are surrounded by ER-negative cells (6, 7, 8, 9) . With increasing age, the number of ER-positive cells increases, such that 30–40% of epithelial cells are ER positive in the postmenopausal breast (9 , 10) . Expression of PgR appears to coincide very closely with that of ER in the luminal epithelium (11 , 12) . Furthermore, there exists an inverse correlation between hormone receptor positivity and cell proliferation in the normal breast epithelium (8 , 10, 11, 12) , suggesting that hormone receptor-positive cells regulate mitogenesis in neighboring cells in a paracrine fashion (13) .

In contrast, the great majority of epithelial cells in preinvasive breast lesions such as atypical hyperplasia and carcinoma in situ are ER positive, and there is a strong correlation between ER positivity and cell proliferation (9 , 10 , 14) . These observations have led to the formulation of a mechanistic model in which ER-positive breast epithelial cells are at higher risk for progression to malignancy and that the development of autonomy from proliferative constraints by ER-expressing epithelial cells represents a critical early event in breast tumorigenesis. Consistent with this model are the observations that ER expression is increased in normal epithelial cells of cancer-bearing breasts (15) and that the proportion of ER-positive breast epithelial cells is lower in women at lower risk for breast cancer (16) .

Data to suggest that hormone receptor expression may differ in BRCA-associated compared with sporadic breast cancers are beginning to emerge. It is well established that ~75% of primary breast cancers generally are classified as ER-positive, although this figure varies with age, race, nodal status, and other prognostic factors (17 , 18) , but the fraction of BRCA1-associated tumors with ER/PgR expression appears to be considerably lower (19, 20, 21, 22, 23) . More notable perhaps is the observation that the majority of preinvasive ductal carcinoma in situ lesions from BRCA1 heterozygotes are ER/PgR negative, in marked contrast to the very high rate of receptor positivity in these lesions from the general population (24) . Taken together, these data suggest that the general model of ER-positive breast epithelial cells developing proliferative autonomy followed by loss of ER expression may occur earlier or more rapidly during the process of breast tumorigenesis in BRCA1 heterozygotes.

In light of this discussion, we suggest that the most parsimonious explanation for the data presented here is that partial loss of BRCA1 function in breast epithelial cells of BRCA1 heterozygotes leads to derepression of ER activity, which results in increased expression of PgR. This is consistent with the established function of BRCA1 in repression of ligand-independent ER-{alpha} signaling activity (25 , 26) , possibly mediated by the cofactors p300 and cAMP-responsive element binding protein (27) . Increased ER activity coupled with increased PgR expression and, presumably, activity, could thus impose a significantly increased risk of tumorigenic progression in normal breast epithelial cells of BRCA1 heterozygotes. In summary, the data presented here provide additional evidence for BRCA1 haploinsufficiency in breast epithelial cells of BRCA1 heterozygotes and have potential implications for chemoprevention in this population of women.


   ACKNOWLEDGMENTS
 
We thank Lee K. Tan, Department of Pathology, Memorial Sloan-Kettering Cancer Center, for her assistance with pathological review of the breast cancer cases studied.


   FOOTNOTES
 
Grant support: The W. M. Keck Foundation, NIH Grant R01 CA71840, the Breast Cancer Research Foundation, and a gift from Helen Frankenthaler.

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.

Note: T. King and M. Gemignani contributed equally to this work.

Requests for reprints: Jeff Boyd, Department of Surgery, Box 201, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. E-mail: boydj{at}mskcc.org

Received 4/14/04. Revised 5/11/04. Accepted 5/26/04.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

  1. Robson ME, Boyd J, Borgen PI, Cody HS. Hereditary breast cancer. Curr Prob Surg, 38: 377-480, 2001.
  2. Foray N, Randrianarison V, Marot D, Perricaudet M, Lenoir G, Feunteun J. Gamma-rays-induced death of human cells carrying mutations of BRCA1 or BRCA2. Oncogene, 18: 7334-42, 1999.[CrossRef][Medline]
  3. Buchholz TA, Wu X, Hussain A, et al Evidence of haplotype insufficiency in human cells containing a germline mutation in BRCA1 or BRCA2. Int J Cancer, 97: 557-61, 2002.[CrossRef][Medline]
  4. Goggins M, Hruban RH, Kern SE. BRCA2 is inactivated late in the development of pancreatic intraepithelial neoplasia. Am J Pathol, 156: 1767-71, 2000.[Abstract/Free Full Text]
  5. Aickin M, Gensler H. Adjusting for multiple testing when reporting research results: the Bonferroni versus Holm methods. Am J Public Health, 86: 726-8, 1996.[Abstract/Free Full Text]
  6. Petersen OW, Hoyer PE, van Deurs B. Frequency and distribution of estrogen receptor-positive cells in normal, nonlactating human breast tissue. Cancer Res, 47: 5748-51, 1987.[Abstract/Free Full Text]
  7. Ricketts D, Turnbull L, Ryall G, et al Estrogen and progesterone receptors in the normal female breast. Cancer Res, 51: 1817-22, 1991.[Abstract/Free Full Text]
  8. Williams G, Anderson E, Howell A, et al Oral contraceptive (OCP) use increases proliferation and decreases oestrogen receptor content of epithelial cells in the normal human breast. Int J Cancer, 42: 206-10, 1991.
  9. Shoker BS, Jarvis C, Sibson DR, Walker C, Sloane JP. Oestrogen receptor expression in the normal and pre-cancerous breast. J Pathol, 188: 237-44, 1999.[CrossRef][Medline]
  10. Shoker BS, Jarvis C, Clarke RB, et al Estrogen receptor-positive proliferating cells in the normal and precancerous breast. Am J Pathol., 155: 1811-5, 1999.[Abstract/Free Full Text]
  11. Clarke RB, Howell A, Potten CS, Anderson E. Dissociation between steroid receptor expression and cell proliferation in the human breast. Cancer Res, 57: 4987-91, 1997.[Abstract/Free Full Text]
  12. Russo J, Ao X, Grill C, Russo IH. Pattern of distribution of cells positive for estrogen receptor alpha and progesterone receptor in relation to proliferating cells in the mammary gland. Breast Cancer Res. Treat, 53: 217-27, 1999.[CrossRef][Medline]
  13. Anderson E. The role of oestrogen and progesterone receptors in human mammary development and tumorigenesis. Breast Cancer Res, 4: 197-201, 2002.[CrossRef][Medline]
  14. Allred DC, Mohsin SK, Fuqua SAW. Histological and biological evolution of human premalignant breast disease. Endocr Relat Cancer, 8: 47-61, 2001.[Abstract]
  15. Khan SA, Rogers MA, Obando JA, Tamsen A. Estrogen receptor expression of benign breast epithelium and its association with breast cancer. Cancer Res, 54: 993-7, 1994.[Abstract/Free Full Text]
  16. Lawson JS, Field AS, Champion S, Tran D, Ishikura H, Trichopoulos D. Low estrogen receptor {alpha} expression in normal breast tissues underlies low breast cancer incidence in Japan. Lancet, 354: 1787-8, 1999.[CrossRef][Medline]
  17. Anderson WF, Chu KC, Chatterjee N, Brawley O, Brinton LA. Tumor variants by hormone receptor expression in white patients with nod-negative breast cancer from the Surveillance, Epidemiology, and End Results database. J Clin Oncol, 19: 18-27, 2001.[Abstract/Free Full Text]
  18. Anderson WF, Chatterjee N, Ershler WB, Brawley OW. Estrogen receptor breast cancer phenotypes in the Surveillance, Epidemiology, and End Results database. Breast Cancer Res Treat, 76: 27-36, 2002.[CrossRef][Medline]
  19. Johannsson OT, Idvall I, Anderson C, et al Tumour biological features of BRCA1-induced breast and ovarian cancer. Eur J Cancer, 33: 362-71, 1997.
  20. Loman N, Johannsson O, Bendahl PO, Borg A, Ferno M, Olsson H. Steroid receptors in hereditary breast carcinomas associated with BRCA1 or BRCA2 mutations in unknown susceptibility genes. Cancer (Phila.), 83: 310-9, 1998.
  21. Robson M, Rajan P, Rosen PP, et al BRCA-associated breast cancer: absence of a characteristic immunophenotype. Cancer Res, 58: 1839-42, 1998.[Abstract/Free Full Text]
  22. Verhoog LC, Brekelmans CT, Seynaeve C, et al Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1. Lancet, 351: 316-21, 1998.[CrossRef][Medline]
  23. Osin P, Gusterson BA, Philp E, et al Predicted anti-oestrogen resistance in BRCA-associated familial breast cancers. Eur J Cancer, 34: 1683-6, 1998.
  24. Osin P, Crook T, Powles T, Peto J, Gusterson B. Hormone status of in situ cancer in BRCA1 and BRCA2 mutation carriers. Lancet, 351: 1487 1998.[CrossRef]
  25. Fan S, Wang J-A, Yuan R, et al BRCA1 inhibition of estrogen receptor signaling in transfected cells. Science (Wash DC), 284: 1354-6, 1999.[Abstract/Free Full Text]
  26. Zheng L, Annab LA, Afshari CA, Lee WH, Boyer TG. BRCA1 mediates ligand-independent transcriptional repression of the estrogen receptor. Proc Natl Acad Sci USA, 98: 9587-92, 2001.[Abstract/Free Full Text]
  27. Fan S, Ma YX, Wang C, et al p300 Modulates the BRCA1 inhibition of estrogen receptor activity. Cancer Res, 62: 141-51, 2002.[Abstract/Free Full Text]



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