Pure Apocrine Carcinomas Research Articles

The assessment of tumor-infiltrating lymphocytes in invasive apocrine carcinoma of the breast in relation to the HER2 status.

In the current study, we assessed the prevalence and molecular features of HER2-low phenotype in the apocrine carcinomas of the breast (ApoCa) and its relationship with tumor-infiltrating lymphocytes (TILs). A cohort of 64 well-characterized therapy-naïve ApoCa was used. The TIL distribution was assessed using the hematoxylin and eosin whole slide/scanned images following the international TILs working group recommendations. Next-generation sequencing (NGS) was performed in a subset of HER2-low ApoCa. All patients were women, with a mean age of 62 years. Forty-three carcinomas were pure apocrine carcinoma (PAC; ER-/AR+), and the remaining 21 were classified as apocrine-like carcinomas (ALCs; ER+/-, AR+/-). HER2/neu was positive (score 3+ by IHC and/or amplified by FISH) in 20/43 (47%) PAC and 4/21 (19%) ALC. The prevalence of HER2-low expression (scores 1+ or 2+ without HER2 amplification) in ApoCa was 39% without significant differences between PAC and ALC (P = 0.14); however, the HER2-low phenotype was more prevalent in triple-negative PAC than in ALC (P < 0.001). Levels of TILs were low (≤10%) in 74% of ApoCa (median 5%, range 0%-50%). TIL levels were significantly higher in ALC than in PAC (P = 0.02). HER2 status had no impact on TIL distribution (P = 0.45). The genomic profile of HER2-low ApoCa was similar to other subtypes of ApoCa. ApoCa has predominantly low TIL, particularly PAC.The prevalence of the HER2-low phenotype in ApoCa is high, which should have therapeutic and clinical implications given the recently approved therapies with antibody-drug conjugates (ADCs) for HER2-low breast cancers.

Clinicopathological Characteristics and Prognosis of Triple-Negative Apocrine Carcinoma: A Case-Control Study.

With a prevalence of only 1% among all breast cancers in Japan, apocrine carcinoma (AC) is a rare type of breast cancer, and its clinicopathological characteristics remain unclear. The aim of this study was to evaluate the characteristics and prognosis of AC, in relation to the presence or absence of androgen receptor (AR). We conducted a retrospective multi-center case-control study (Yokohama Clinical Oncology Group (YCOG): YCOG1701 study) in Japan. A total of 53 patients were registered who were diagnosed with AC between 2000 and 2017 in YCOG-affiliated hospitals. The median age of the patients was 67 (43 - 94) years, and the median observation time was 6.1 years. Among the 53 cases, 24 had triple-negative pure AC (TN-PAC; AR-positive), whereas 29 had other types of AC (other-AC; estrogen receptor-positive and/or human epidermal growth factor receptor 2-positive or AR-negative). Tumor size was smaller (1.4 vs. 2.1 cm, P = 0.024) and metastasis occurred in fewer nodes (12.5% vs. 37.9%, P = 0.036) in the TN-PAC group than in the other-AC group. The number of patients who were administered perioperative adjuvant chemotherapy did not significantly differ between the two groups (TN-PAC/other-AC = 50.0%/55.2%, P = 0.525); however, there was no recurrence in the TN-PAC group, compared to five cases with relapse in the other-AC group. AR-positive AC patients showed a favorable prognosis without adjuvant chemotherapy, even with the TN subtype. A clinical trial exploring the possibility of treatment de-escalation is anticipated.

Apocrine carcinoma of the breast: Review

Abstract Apocrine carcinoma of the breast is a rare subtype of breast carcinoma, which only presents as 4% among patients with breast cancer. The percentage varies based on the diagnostic criteria used by each institution to classify apocrine carcinoma. Several confusing terms used in previous studies, including apocrine ductal carcinoma in situ (ADCIS), apocrine morphology in lobular carcinoma in situ (Apocrine LCIS), apocrine-like invasive carcinoma, pure apocrine carcinoma, molecular apocrine tumors (MATs), and triple-negative apocrine carcinoma of the breast (TNAC). The treatment, prognosis, and molecular profiles are also diverse. Pure apocrine carcinoma has stricter criteria for diagnosis, requiring more than 90% of cells showing apocrine morphology and classic IHC characteristics of ER-negative, PR-negative, and AR-positive in at least 10% of tumor cell nuclei. Research related to prognosis is diverse due to the difficulty of unifying the diagnostic criteria. Current evidence of treatment is geared toward the use of neoadjuvant chemotherapy and anti-androgen therapy when AR is present, accompanied by other treatments if biomarkers are present, such as HER2, PI3K, or CDK4/6. This article focuses on clearly summarizing different subtypes and management of apocrine carcinoma of the breast.

Triple-Negative Apocrine Carcinomas: Toward a Unified Group With Shared Molecular Features and Clinical Behavior

Triple-negative apocrine carcinomas (TNACs) are rare breast tumors with limited studies evaluating their molecular characteristics and clinical behavior. We performed a histologic, immunohistochemical, genetic, and clinicopathologic assessment of 42 invasive TNACs (1 with a focal spindle cell component) from 41 patients, 2 pure apocrine ductal carcinomas in situ (A-DCIS), and 1 A-DCIS associated with spindle cell metaplastic carcinoma (SCMBC). All TNACs had characteristic apocrine morphology and expressed androgen receptor (42/42), gross cystic disease fluid protein 15 (24/24), and CK5/6 (16/16). GATA3 was positive in most cases (16/18, 89%), and SOX10 was negative (0/22). TRPS1 was weakly expressed in a minority of tumors (3/14, 21%). Most TNACs had low Ki67 proliferation (≤10% in 67%, 26/39), with a median index of 10%. Levels of tumor infiltrating lymphocytes were low (≤10% in 93%, 39/42, and 15% in 7%, 3/42). Eighteen percent of TNACs presented with axillary nodal metastasis (7/38). No patients treated with neoadjuvant chemotherapy achieved pathologic complete response (0%, 0/10). Nearly all patients with TNAC (97%, n = 32) were without evidence of disease at the time of study (mean follow-up of 62 months). Seventeen invasive TNACs and 10 A-DCIS (7 with paired invasive TNAC) were profiled by targeted capture-based next-generation DNA sequencing. Pathogenic mutations in phosphatidylinositol 3-kinase pathway genes PIK3CA (53%) and/or PIK3R1 (53%) were identified in all TNACs (100%), including 4 (24%) with comutated PTEN. Ras-MAPK pathway genes, including NF1 (24%), and TP53 were mutated in 6 tumors each (35%). All A-DCIS shared mutations, such as phosphatidylinositol 3-kinase aberrations and copy number alterations with paired invasive TNACs or SCMBC, and a subset of invasive carcinomas showed additional mutations in tumor suppressors (NF1, TP53, ARID2, and CDKN2A). Divergent genetic profiles between A-DCIS and invasive carcinoma were identified in 1 case. In summary, our findings support TNAC as a morphologically, immunohistochemically, and genetically homogeneous subgroup of triple-negative breast carcinomas and suggest overall favorable clinical behavior.

Tumor-infiltrating lymphocytes status, programmed death-ligand 1 expression, and clinicopathological features of 41 cases of pure apocrine carcinoma of the breast: a retrospective study based on clinical pathological analysis and different immune statuses.

Pure apocrine carcinoma (AC) of the breast can be divided into human epidermal growth factor receptor-2 (HER2)-positive and triple-negative apocrine carcinoma (TNAC). Some studies showed that triple negative breast cancer with low tumor-infiltrating lymphocytes (TILs) and high programmed death-ligand 1 (PD-L1) status may be a therapeutic target for immune checkpoint inhibitors. However, the clinicopathological features of different HER2 expression, TILs status and PD-L1 expression in AC are not clear. Therefore, we investigate the status of TILs and PD-L1, as well as the clinicopathological features of pure apocrine carcinoma of the breast. We retrospectively analyzed the clinicopathological data, and prognosis of 41 cases of pure apocrine carcinoma of the breast that underwent surgical resection from January 2014 to November 2020. TILs were evaluated. Immunohistochemistry (IHC) staining was applied to detect PD-L1 protein expression in 14 of these samples from January 2019 to November 2020. The expression and correlation of HER2, TILs, PD-L1 and clinicopathological features and prognoses were analyzed. A total of 80.5% (33/41) of patients had TILs <50%, and 19.5% (8/41) had TILs ≥50%. The expression of TILs and the Ki-67 proliferation index were significantly higher in the HER2-positive group (41.5%, 17/41) compared to the HER2-negative group (58.5%, 24/41) (P<0.05). Approximately 52.9% (9/17) of HER2-positive patients treated with Trastuzumab targeted therapy, overall survival was higher in HER2-positive patients than in HER2-negative patients (P=0.211). The PD-L1 positivity rate was 50% (7/14) in the 14 pure apocrine carcinoma of the breast samples, and 66.7% (4/6) and 37.5% (3/8) in the HER2-negative and HER2-positive groups, respectively, with no significant difference (P=0.592). Among these 14 cases, two samples had TILs ≥50%, both of which were positive for PD-L1 and Ki67 >20%; and 12 cases had TILs <50%, of which 41.7% (5/12) were PD-L1-positive and 58.3% (7/12) were PD-L1-negative. All 14 cases with PD-L1-negative had TILs <50%. There was no significant difference in overall survival between TILs and Ki67 co-expression (P=0.452). Pure AC HER2-positive patients have higher levels of TILs and Ki67, HER2 negative and TILs ≥50% patients may have higher PD-L1 expression, which may be helpful for screening patients with different immune statuses to guide effective clinical treatment combinations.

Apocrine lesions of the breast: part 2 of a two-part review. Invasive apocrine carcinoma, the molecular apocrine signature and utility of immunohistochemistry in the diagnosis of apocrine lesions of the breast

Pure apocrine carcinoma of the breast is rare and has been defined by using a combination of morphologic (apocrine morphology in >90% of tumour cells) and immunohistochemical criteria (oestrogen receptor...

Apocrine lesions of the breast: part 1 of a two-part review: benign, atypical and in situ apocrine proliferations of the breast

Apocrine morphology is a common phenomenon encountered in everyday breast pathology practice, and is defined as cuboidal or columnar cells exhibiting abundant eosinophilic granular cytoplasm, prominent apical granules, a low...

Abstract P6-09-07: Triple negative apocrine carcinomas as a distinct subtype of triple negative breast cancer: A case-control study

Abstract Introduction. Invasive apocrine carcinoma of the breast is a rare type of breast cancer (BC), pure apocrine carcinoma constitutes &amp;lt;1% of all BC. Mammary apocrine epithelium has a characteristic steroid receptor profile that is negative for full length estrogen receptor-alpha and progesterone receptor and is androgen receptor positive. Conflicting data are available on the outcome of this type of disease: few studies reported significantly different prognosis of triple negative (TN) apocrine carcinomas when compared to most non-apocrine triple negative (NA-TN) tumors. The aim of this study is to report our long-term experience in a single-center series of TN apocrine tumors. Methods. We analyzed clinical and pathological features of a series of TN apocrine carcinomas treated at our Centre in a 15-year period. Clinical and pathological characteristics and outcomes have been compared with a control series of NA-TN tumors treated during the same follow up period. Local relapse-free survival (LRFS), distant metastases-free survival (DMFS), and overall survival (OS) have been evaluated and compared between groups of patients. Results. Forty-five TN apocrine carcinomas were analyzed. The mean age at diagnosis was 60 years (range 34-83 years). The proportions of apocrine tumor grades varied, with G1 being seen in 6.8% of patients, G2 in 51.1%, and G3 in 40.1%. The majority of apocrine carcinomas had small tumor size (T1: 72.7%; T2: 27.3%), and negative axillary nodal status (66.7%). The series was compared to a homogenous control group of 45 NA-TN patients. The mean age was 54 years (range 32-79 years), affected by high grade (G3: 53.7%), small tumor size (T1: 87.5%; T2: 12.5%), and mostly negative axillary nodal status (82.9%). LRFS in the apocrine group was 85% and 78% at 5- and 10-year, respectively. LRFS in the NA-TN group was 90% and 79% at 5- and 10-year, respectively. No difference was evidenced between groups (HR 1.44 95%CI 0.62-3.79; p=0.39). DMFS in the apocrine group was 85% and 85% at 5- and 10-years, respectively. DMFS in the NA-TN group was 85% and 75% at 5- and 10-year, respectively. DMFS was significantly better in the apocrine group (HR 0.69 95%CI 0.28-1.62). OS in the apocrine group was 86% and 83% at 5- and 10-year, respectively. OS in the NA-TN group was 86% and 63% at 5- and 10-years, respectively. OS was significantly better in the apocrine group (HR 0.57 95%CI 0.26-1.18). Conclusions. Apocrine carcinomas represent a clinic-pathological distinct group of triple-negative BC, characterized by significantly more favorable clinical prognosis in terms of long-term disease-related morbidity or mortality when compared to NA-TN tumors. Citation Format: Meattini I, Pezzulla D, Carta GA, Becherini C, Perna M, Grassi R, Garlatti P, Desideri I, Scotti V, Bernini M, Sanchez LJ, Orzalesi L, Nori J, Bianchi S, Livi L. Triple negative apocrine carcinomas as a distinct subtype of triple negative breast cancer: A case-control study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-09-07.

Pure Apocrine Carcinomas Represent a Clinicopathologically Distinct Androgen Receptor-Positive Subset of Triple-Negative Breast Cancers.

Apocrine carcinomas comprise ∼1% of all breast cancers and are characterized by large cells bearing abundant eosinophilic granular cytoplasm, round nuclei, and prominent nucleoli. They are typically estrogen receptor/progesterone receptor/HER2 negative, making them unresponsive to typical hormonal or HER2-based chemotherapy. However, this subtype of triple-negative breast cancers expresses androgen receptor (AR), a feature not shared by most nonapocrine triple-negative cancers (NA-TNCs). AR therefore represents a potential diagnostic tool and therapeutic target for apocrine breast carcinoma. All pure apocrine carcinomas diagnosed during a 10-year period were reviewed, and clinicopathologic characteristics were compared with a control group of 26 NA-TNC cases. Twenty apocrine carcinomas were identified (∼0.8% of all breast cancers). The mean age at diagnosis was 69.3 years for apocrine carcinomas and 56.7 years for NA-TNC. All apocrine carcinomas and no NA-TNC were AR positive. The proportions of apocrine carcinoma grades varied, with G1 being seen in 15% of patients, G2 in 55%, and G3 in 30%. In contrast, 100% of NA-TNC cases were G3. The majority of apocrine carcinomas presented at low T stage (T1: 70%; T2: 20%; T3: 10%; T4: 0%), whereas NA-TNC cases more often presented at T2 or higher (T1: 46.2%; T2: 30.8%; T3: 11.5%; T4: 11.5%). Thirty percent of apocrine carcinomas and 30.8% of NA-TNCs had nodal metastases at presentation. Apocrine carcinomas had a favorable clinical prognosis, with 80% of patients showing no evidence of disease-related morbidity or mortality (mean follow-up: 45.2 mo). Pure apocrine carcinomas represent a clinicopathologically distinct subgroup of triple-negative breast cancer characterized by AR positivity. When compared with NA-TNC, apocrine carcinomas more often present in older women with lower grade and T stage, a group in which a more conservative treatment regimen is often desired.

Immunohistochemically Defined Subtypes and Outcome of Apocrine Breast Cancer

BackgroundConflicting data are available in the literature on the outcome of invasive apocrine carcinoma (IAC), possibly related to a heterogeneous classification of these tumors. Patients and MethodsA series of 6899 consecutive patients with invasive ductal carcinoma (IDC) not otherwise specified and 72 patients with immunohistochemically defined IAC who received surgery at the European Institute of Oncology between 1997 and 2005 were included. We then explored patterns of recurrence of IAC according to 2 immunohistochemically defined tumor subtypes: pure apocrine carcinoma (estrogen [ER] and progesterone [PgR] receptor negative, and AR positive) and apocrine-like carcinoma (ER or PgR positive and AR negative). ResultsThe diagnosis of pure apocrine carcinoma was correlated with a worse outcome in terms of DFS (hazard ratio [HR] 1.7; 95% confidence interval [CI], 1.01-2.86; P = .0010) if compared with IDC, whereas IDC and apocrine-like breast cancers showed a similar outcome in terms of DFS and overall survival. Patients with pure apocrine carcinoma had an increased risk in contralateral breast cancer (HR, 4.12; 95% CI, 1.22-14; P = .02). ConclusionPure apocrine carcinoma represents a distinct subtype of breast cancer with a significantly worse DFS as compared with IDC. AR determination might have an important prognostic implication in IAC. Moreover, AR-targeted therapy should be further explored within these tumors.

"Pure" invasive apocrine carcinoma of the breast with psammoma bodies

Pure apocrine carcinomas are rare, morphologically distinct type of invasive of breast carcinomas, and represent about 0.5% of all invasive breast cancers. Existence of psammoma bodies (PBs) is extremely rare. Cytological, histological and immunohistochemical features of a case of apocrine carcinoma of the breast with PBs is described in a 56-year-old female. This report emphasizes the rarity of this lesion and supports currently held beliefs about the formation of PBs.

ER-α36, a novel isoform of ER-α66, is commonly over-expressed in apocrine and adenoid cystic carcinomas of the breast

BackgroundER-α36 is a novel 36 kDa isoform of the full-length oestrogen receptor alpha (ER-α66). ER-α36 primarily localises to the cytoplasm and the plasma membrane, and responds to membrane-initiated oestrogen and...

EGFR and HER-2/neu expression in invasive apocrine carcinoma of the breast

This study was undertaken to investigate epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER-2)/neu expression in a cohort of apocrine carcinomas of the breast with emphasis on the classification of the breast tumors with apocrine morphology. In total, 55 breast carcinomas morphologically diagnosed as apocrine were evaluated for the steroid receptor expression profile characteristic of normal apocrine epithelium (androgen receptor positive/estrogen receptor (ER) negative/progesterone receptor (PR) negative), and for the expression of EGFR and Her-2/neu proteins, and the copy number ratios of the genes EGFR/CEP7 and HER-2/CEP17. On the basis of the results of steroid receptors expression, 38 (69%) cases were classified as pure apocrine carcinoma (androgen receptor positive/ER negative/PR negative), whereas 17 (31%) were re-classified as apocrine-like carcinomas because they did not have the characteristic steroid receptor expression profile. Her-2/neu overexpression was observed in 54% of the cases (57% pure apocrine carcinomas vs 47% apocrine-like carcinomas). HER-2/neu gene amplification was demonstrated in 52% of all cases (54% pure apocrine carcinomas vs 46% apocrine-like carcinomas). EGFR protein (scores 1 to 3+) was detected in 62% of all cases and was expressed in a higher proportion of pure apocrine carcinomas than in the apocrine-like carcinomas group (76 vs 29%, P=0.006). In the pure apocrine carcinoma group, Her-2/neu and EGFR protein expression were inversely correlated (P=0.006, r=−0.499). EGFR gene amplification was observed in two pure apocrine carcinomas and one apocrine-like carcinoma. Polysomy 7 was commonly present in pure apocrine carcinomas (61 vs 27% of apocrine-like carcinomas; P=0.083) and showed a weak positive correlation with EGFR protein expression (P=0.025, r=0.326). Our study showed that apocrine breast carcinomas are molecularly diverse group of carcinomas. Strictly defined pure apocrine carcinomas are either HER-2-overexpressing breast carcinomas or triple-negative breast carcinomas, whereas apocrine-like carcinomas predominantly belong to the luminal phenotype. Pure apocrine carcinomas show consistent overexpression of either EGFR or HER-2/neu, which could have significant therapeutic implications.

Pure apocrine carcinomas of the breast express ER-alpha 36, a novel alternatively spliced variant of human estrogen receptor-alpha (ER-alpha 66).

Abstract Abstract #4035 Background: Pure apocrine carcinomas (PACs) are defined as tumors composed entirely of epithelium showing apocrine differentiation (large cells with prominent eosinophilic, flocculent cytoplasm with sharply defined borders and large nucleus with prominent macronucleolus). PACs do not express classic estrogen receptor alpha (ER-α66) or progesterone receptor (PR) but consistently over-expresses androgen receptor (AR). We have investigated expression of a novel alternatively spliced variant of ER-α66, named ER-α36, which we recently identified and cloned (Wang ZY et al, PNAS 2006;103: 9063) and demonstrated that it mediates membrane initiated steroid signaling (MISS). MISS is dependent on ER interaction with receptor tyrosine kinases, and we hence investigated co-expression of ER-α36 with EGFR and HER2 in PACs.&amp;#x2028; Methods: 17 patients with breast PAC were studied for expression of ER-α66, PR, AR, HER-2, EGFR and ER-α36 using immunohistochemical methods. ER-α36-specific antibody was custom-made by the Alpha Diagnostic International (San Antonio, TX) against the unique 20 amino acids at the C-terminal of the ER-a36; other antibodies were from commercially available sources. Mammary carcinoma cell line (MDA-MB-231) that lacks expression of ER-α66 but expresses ER-α36 and EGFR, was used as a positive control.&amp;#x2028; Results: All tumors showed characteristic steroid receptor expression profile of apocrine carcinomas (ERα66 and PR negative; AR strongly positive). ERα36 expression was detected in 16/17 cases (94%) in membranous and cytoplasmic distribution. Co-expression of ER-α36 with either one of the tyrosine kinase receptors (HER2 or EGFR) was detected in 16 cases (100% of ER-α36 positive PACs). In an experimental model (MDA-MB-231 cells), 17β-estradiol (E2) strongly induced rapid phosphorylation of the MAPK/ERK1/2, but had only a weak effect in ER-α36 siRNA knock-down MDA-MB-231 cells.&amp;#x2028; Conclusion: Despite the lack of classic full length ER-alpha expression (ER-α66) in PACs, a novel alternatively splice variant (ER-α36) is commonly expressed in this aggressive tumor type. This receptor variant is capable of strong E2 signal transduction and responsible for an increased cell growth. This non-genomic estrogen signaling probably involves membranous interaction between a tyrosine kinase receptor (EGFR or HER2) and ER-α36, resulting in activation of mitogen activated protein kinase pathway. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4035.

Molecular pathology of breast apocrine carcinomas: A protein expression signature specific for benign apocrine metaplasia

Breast cancer is a heterogeneous disease that encompasses a wide range of histopathological types including: invasive ductal carcinoma, lobular carcinoma, medullary carcinoma, mucinous carcinoma, tubular carcinoma, and apocrine carcinoma among others. Pure apocrine carcinomas represent about 0.5% of all invasive breast cancers according to the Danish Breast Cancer Cooperative Group Registry, and despite the fact that they are morphologically distinct from other breast lesions, there are at present no standard molecular criteria available for their diagnosis. In addition, the relationship between benign apocrine changes and breast carcinoma is unclear and has been a matter of discussion for many years. Recent proteome expression profiling studies of breast apocrine macrocysts, normal breast tissue, and breast tumours have identified specific apocrine biomarkers [15-hydroxyprostaglandin dehydrogenase (15-PGDH) and hydroxymethylglutaryl coenzyme A reductase (HMG-CoA reductase)] present in early and advanced apocrine lesions. These biomarkers in combination with proteins found to be characteristically upregulated in pure apocrine carcinomas (psoriasin, S100A9, and p53) provide a protein expression signature distinctive for benign apocrine metaplasias and apocrine cystic lesions. These studies have also presented compelling evidence for a direct link, through the expression of the prostaglandin degrading enzyme 15-PGDH, between early apocrine lesions and pure apocrine carcinomas. Moreover, specific antibodies against the components of the expression signature have identified precursor lesions in the linear histological progression to apocrine carcinoma. Finally, the identification of proteins that characterize the early stages of mammary apocrine differentiation such as 15-PGDH, HMG-CoA reductase, and cyclooxygenase 2 (COX-2) has opened a window of opportunity for pharmacological intervention, not only in a therapeutic manner but also in a chemopreventive setting. Here we review published and recent results in the context of the current state of research on breast apocrine cancer.

Apocrine Cysts of the Breast

Up to one-third of women aged 30-50 years have cysts in their breasts and are presumed to be at increased risk of developing breast cancer. Here we present an extensive proteomic and immunohistochemistry (IHC) study of breast apocrine cystic lesions aimed at generating specific biomarkers and elucidating the relationship, if existent, of apocrine cysts with cancer phenotype. To this end we compared the expression profiles of apocrine macrocysts obtained from mastectomies from high risk cancer patients with those of cancerous and non-malignant mammary tissue biopsies collected from the same patients. We identified two biomarkers, 15-hydroxyprostaglandin dehydrogenase and 3-hydroxymethylglutaryl-CoA reductase, that were expressed specifically by apocrine type I cysts as well as by apocrine metaplastic cells in type II microcysts, terminal ducts, and intraductal papillary lesions. No expression of these markers was observed in non-malignant terminal ductal lobular units, type II flat cysts, stroma cells, or fat tissue as judged by IHC analysis of matched non-malignant tissue samples collected from 93 high risk patients enrolled in our cancer program. IHC analysis of the corresponding 93 primary tumors indicated that most apocrine changes have little intrinsic malignant potential, although some may progress to invasive apocrine cancer. None of the apocrine lesions examined, however, seemed to be a precursor of invasive ductal carcinomas, which accounted for 81% of the tumors analyzed. Our studies also provided some insight into the origin, development, and enlargement of apocrine cysts in mammary tissue. The successful identification of differentially expressed proteins that characterize specific steps in the progression from early benign lesions to apocrine cancer opens a window of opportunity for designing and testing new approaches for pharmacological intervention, not only in a therapeutic setting but also for chemoprevention, to inhibit cyst development as both 15-hydroxyprostaglandin dehydrogenase and 3-hydroxymethylglutaryl-CoA reductase are currently being targeted for chemoprevention strategies in various malignancies.

Androgen and estrogen receptor mRNA status in apocrine carcinomas.

Eleven pure apocrine carcinomas (8 breast, 2 vulvar, 1 axillary) were evaluated for the presence of androgen and estrogen receptor mRNA. These immunohistochemically androgen receptor positive and estrogen receptor negative cases were microdissected and analyzed by the reverse transcription polymerase chain reaction for the presence of receptor message. Nine of these 11 estrogen receptor (ER) negative lesions were found to contain the ER mRNA through the first intron splice region. In 4 of the 11 cases, the androgen receptor (AR) mRNA could not be shown even though the protein was detected immunohistochemically. In the other seven, AR mRNA was identified. This indicates that the mechanism for production of the estrogen receptor is intact and functional in most cases through the first transcriptional splice region. Therefore, the immunohistochemical absence of the estrogen receptor in apocrine cells cannot be explained by an abnormal message at these common sites and should be sought beyond these points.