Typical medullary carcinoma of the breast: A clinical and pathological analysis of 52 cases

Multiple different oncogenes have been described previously to be amplified in breast cancer including HER2, EGFR, MYC, CCND1, and MDM2. Gene amplification results in oncogene overexpression but may also serve as an indicator of genomic instability. As such, presence of one or several gene amplifications may have prognostic significance. To assess the prognostic importance of amplifications and coamplifications of HER2, EGFR, MYC, CCND1, and MDM2 in breast cancer, we analyzed a breast cancer tissue microarray containing samples from 2197 cancers with follow-up information. Fluorescence in situ hybridizations revealed amplifications of CCND1 in 20.1%, HER2 in 17.3%, MDM2 in 5.7%, MYC in 5.3%, and EGFR in 0.8% of the tumors. All gene amplifications were significantly associated with high grade. HER2 (P < 0.001) and MYC amplification (P < 0.001) were also linked to shortened survival. In case of HER2, this was independent of grade, pT, and pN categories. MYC amplification was almost 3 times more frequent in medullary cancer (15.9%), than in the histologic subtype with the second highest frequency (ductal; 5.6%; P ‫؍‬ 0.0046). HER2 and MYC amplification were associated with estrogen receptor/progesterone receptor negativity (P < 0.001) whereas CCND1 amplification was linked to estrogen receptor/progesterone receptor positivity (P < 0.001). Coamplifications were more prevalent than expected based on the individual frequencies. Coamplifications of one or several other oncogenes occurred in 29.6% of CCND1, 43% of HER2, 55.7% of MDM2, 65% of MYC, and 72.8% of EGFR-amplified cancers. HER2/MYC-coamplified cancers had a worse prognosis than tumors with only one of these amplifications. Furthermore, a gradual decrease of survival was observed with increasing number of amplifications. In conclusion, these data support a major prognostic impact of genomic instability as determined by a broad gene amplification survey in breast cancer.

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“…53), KIT overexpression (54), and (despite its high grade phenotype and high Ki67 labeling index; ref. 55), a relatively good prognosis (56).…”

Section: Discussionmentioning

confidence: 99%

Prognostic Relevance of Gene Amplifications and Coamplifications in Breast Cancer

et al. 2004

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“…Mutations of BRCA1 have been linked to approximately 45% of familial breast cancers and more than 80% of familial ovarian cancers (Easton et al, 1993), although mutations of BRCA1 in sporadic breast cancer appears to be a very rare event (Chen et al, 1995;Miki et al, 1994), to date observed only in typical medullary carcinomas (2/18) (Eisinger et al, 1998), a rare form which carries a low risk of lymph node involvement (Rapin et al, 1998;Reinfuss et al, 1995). The role of BRCA1 in sporadic breast cancer has therefore been equivocal (Vogelstein and Kinzler, 1994;Boyd, 1995), although in vitro studies clearly indicate a tumour suppressive role for BRCA1 (Thompson et al, 1995;Holt et al, 1996) and early studies of subcellular localization of BRCA1 indicated aberrant localization in sporadic breast tumours (Chen et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

BRCA1 expression levels predict distant metastasis of sporadic breast cancers

et al. 1999

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The role of BRCA1 in progression of sporadic breast cancers has to date been equivocal, although preliminary studies on small numbers of samples have suggested an association between expression levels of this gene and acquisition of an invasive phenotype. We have further reasoned that loss of oestrogen receptor positivity may have a detrimental effect on BRCA1 expression. In order to test this hypothesis and extend earlier investigations we have applied a sensitive RT-PCR procedure to determine the associations between BRCA1 expression and a variety of clinical parameters in a sample cohort derived from sporadic breast tumour specimens. We have established that BRCA1 and ER mRNA expression are closely associated (pϭ0.013), indicating a possible functional relationship between these 2 genes. We have further identified an association between low levels of BRCA1 expression and acquisition of distant metastasis in sporadic disease (pϭ0.019). In light of our findings, we suggest that suppression of BRCA1 has a role to play in progression of a significant fraction of sporadic breast cancers and may additionally prove to be a useful, novel, prognostic marker for this disease type. Int. J. Cancer (Pred. Oncol.) 84:258-262, 1999. Wiley-Liss, Inc.Breast cancer is one of the commonest malignancies in women, occurring in both hereditary and sporadic forms. About 5-10% of all cases are estimated to be familial. Of these, approximately 45% are attributable to germline mutations in one gene, BRCA1 (Miki et al., 1994;Easton et al., 1993Easton et al., , 1995. Mutations in BRCA1 also account for more than 75% of familial breast/ovarian cancers (Narod et al., 1995). In the breast, BRCA1 expression is specific to epithelial cells and is found at highest levels in terminal end buds during puberty and in developing alveoli during pregnancy (Marquis et al., 1995). Inhibition of BRCA1 expression leads to accelerated growth of both normal and malignant breast cancer cells (Thompson et al., 1995). Conversely overexpression of BRCA1 in breast cancer cell lines inhibits their growth in vitro and also inhibits their ability to form tumours in nude mice (Holt et al., 1996). In line with these observations, elevated expression of BRCA1, induced by retroviral infection of xenograft tumours, markedly improves long-term survival rates (Holt et al., 1996), suggesting that BRCA1 may function as a tumour suppressor. BRCA1 growth inhibition is cell-cycle dependent, and unlike other growth regulators such as p53 and pRb, is also cell-type specific (Holt et al., 1996). The cell specificity of BRCA1 growth inhibition suggests that analogues of this protein, or BRCA1-based gene therapy, may be of utility in treatment of sporadic as well as familial breast cancers (Holt et al., 1996). BRCA1 mRNA levels are indirectly elevated in breast cancer cells in response to oestrogen (Spillman and Bowcock, 1996;Marks et al., 1997) and a synergistic induction of BRCA1 expression is observed in ovariectomized mice treated with 17␤-oestradiol and progesterone (Marquis...

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“…Among these, medullary carcinoma of the breast (MCB) 4 represents a minor morphologically and biologically distinct group (3-7% of breast cancer) that, despite cytologically anaplastic features, has a more favorable prognosis than other types of breast cancer at similar stages of differentiation. In multiple studies the 10-year survival of MCB patients has been ϳ84 vs 63% for ductal breast cancer patients (1)(2)(3)(4)(5)(6). MCB is characterized by prominent lymphoplasmacytic infiltrates in the tumor stroma.…”

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confidence: 99%

Translocation of an Intracellular Antigen to the Surface of Medullary Breast Cancer Cells Early in Apoptosis Allows for an Antigen-Driven Antibody Response Elicited by Tumor-Infiltrating B Cells

Hansen

Nielsen

Ditzel

2002

The Journal of Immunology

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Tumor-infiltrating lymphoplasmacytic cells are a key feature of medullary carcinoma of the breast (MCB), a distinct subtype of human breast cancer that, despite cytologically anaplastic characteristics, has a more favorable prognosis than other types of breast cancer. Since it has been proposed that the improved clinical outcome is due at least in part to the presence of a prominent lymphoplasmacytic cell infiltrate in the tumor stroma, we recently examined the tumor-infiltrating B cell response in MCB and showed that it is oligoclonal and directed against an intracellular protein translocated to the cell surface upon MCB cell apoptosis. Human Abs cloned from MCB lymphoplasmacytic infiltrate-derived phage display libraries and reflecting the dominant part of the response were used to identify the target Ag as actin. Here, we have characterized in detail the cloned human IgG Abs and the translocation process of actin to the cell surface of apoptotic MCB cells. Our analysis shows that the cloned Abs bind specifically and with high affinity to actin, as determined by ELISA and surface plasmon resonance. Sequence analysis revealed that the Abs are highly somatically mutated, with high replacement to silent ratios, indicative of an Ag-driven, affinity-matured response. Interestingly, the tumor-infiltrating B cells in half the MCB patients mainly exhibited an IgG2 response, while IgG1 dominated in the others. To gain insight to the molecular events that may elicit such an Ab response, we examined the translocation of actin to the cell surface of apoptotic MCB cells using flow cytometry and laser scanning cytometry. Our results show that actin becomes exposed on the cell surface of a large proportion of apoptotic MCB cells as an early apoptotic event. We propose that the Ab response against actin produced by tumor-infiltrating B lymphoplasmacytic cells is Ag-driven, affinity-matured, and elicited due to the increased rate of apoptosis occurring within the MCB tumor that facilitates the translocation and proteolytic fragmentation of intracellular proteins.

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Typical medullary carcinoma of the breast: A clinical and pathological analysis of 52 cases

Cited by 49 publications

References 19 publications

Prognostic Relevance of Gene Amplifications and Coamplifications in Breast Cancer

Prognostic Relevance of Gene Amplifications and Coamplifications in Breast Cancer

BRCA1 expression levels predict distant metastasis of sporadic breast cancers

Translocation of an Intracellular Antigen to the Surface of Medullary Breast Cancer Cells Early in Apoptosis Allows for an Antigen-Driven Antibody Response Elicited by Tumor-Infiltrating B Cells

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