Breast carcinoma metastasis within granulosa cell tumor of the ovary: morphologic, immunohistologic, and molecular analyses of the two different tumor cell populations.

Gynecologic metastasis of breast carcinoma is not an infrequent event, but metastases within another tumor is very rare. We report a case of unilateral ovarian tumor arising in a 63-year-old woman receiving tamoxifen therapy with a past history of breast carcinoma. The microscopic appearance was principally that of a granulosa cell tumor, but the presence of atypical cells closely admixed within the classical areas was reminiscent of metastasis from breast carcinoma. The diagnosis of this first reported case of breast carcinoma metastasis within granulosa cell tumor was supported by immunohistologic analysis. The diagnosis of tumor-to-tumor metastasis was also confirmed by molecular study using microdissections of samples from the initial breast tumor and from the subsequent ovarian tumor. When compared with normal tissue, carcinomatous cells in the breast tissue exhibited genomic abnormality at the same locus as the metastatic cells in the ovary. In contrast, granulosa cell tumor areas did not show any loss of heterozygosity or instability for the microsatellites analyzed.

Comparative analysis of molecular alterations in fibroadenomas associated or not with breast cancer.

HYPOTHESIS: The cause of breast cancer is linked to many macroscopic events, including benign breast disease. In this study we asked whether molecular changes could discriminate fibroadenoma, which is one of the most common benign breast disease lesions associated or not with breast cancer. DESIGN: Retrospective cohort study. SETTING: Anticancer medical center. SUBJECTS: Archival tissues in 32 cases of fibroadenoma, diagnosed in the same breast as a breast carcinoma, are compared with a control group of 26 cases of fibroadenomas unaffected by breast cancer. MAIN OUTCOME MEASURES: Histological features are characterized in all samples. The epithelial and stromal components are analyzed for a loss of heterozygosity and a microsatellite instability using a polymerase chain reaction-based method with 11 polymorphic microsatellite markers at 7 chromosomal regions frequently altered in breast cancer. The p53 gene mutations were also determined at exons 5 to 9. RESULTS: The frequency of complex fibroadenomas was similar in both groups (P =.42). Only in the case group did we observe proliferative lesions confined in fibroadenomas, including atypical ductal hyperplasia (2 cases), lobular neoplasia (3 cases), or low-grade ductal carcinoma in situ (2 cases). There is no significant morphological difference between the 2 groups. Neither microsatellite alterations nor p53 gene mutations are present in the fibroadenoma components. Loss of heterozygosity is found only in the epithelial component of the 2 ductal carcinomas in situ confined in fibroadenomas. CONCLUSIONS: Genetic alterations, which are most frequently involved in malignant breast carcinomas, are not present in fibroadenomas, regardless of their association with breast cancer or their histological complexity. These findings suggest that fibroadenomas are not associated with breast carcinogenesis.

Identification of heparin-binding EGF-like growth factor (HB-EGF) as a biomarker for lysophosphatidic acid receptor type 1 (LPA1) activation in human breast and prostate cancers.

Lysophosphatidic acid (LPA) is a natural bioactive lipid with growth factor-like functions due to activation of a series of six G protein-coupled receptors (LPA1₋6). LPA receptor type 1 (LPA1) signaling influences the pathophysiology of many diseases including cancer, obesity, rheumatoid arthritis, as well as lung, liver and kidney fibrosis. Therefore, LPA1 is an attractive therapeutic target. However, most mammalian cells co-express multiple LPA receptors whose co-activation impairs the validation of target inhibition in patients because of missing LPA receptor-specific biomarkers. LPA1 is known to induce IL-6 and IL-8 secretion, as also do LPA2 and LPA3. In this work, we first determined the LPA induced early-gene expression profile in three unrelated human cancer cell lines expressing different patterns of LPA receptors (PC3: LPA1,2,6; MDA-MB-231: LPA1,2; MCF-7: LPA2,6). Among the set of genes upregulated by LPA only in LPA1-expressing cells, we validated by QPCR and ELISA that upregulation of heparin-binding EGF-like growth factor (HB-EGF) was inhibited by LPA1-3 antagonists (Ki16425, Debio0719). Upregulation and downregulation of HB-EGF mRNA was confirmed in vitro in human MDA-B02 breast cancer cells stably overexpressing LPA1 (MDA-B02/LPA1) and downregulated for LPA1 (MDA-B02/shLPA1), respectively. At a clinical level, we quantified the expression of LPA1 and HB-EGF by QPCR in primary tumors of a cohort of 234 breast cancer patients and found a significantly higher expression of HB-EGF in breast tumors expressing high levels of LPA1. We also generated human xenograph prostate tumors in mice injected with PC3 cells and found that a five-day treatment with Ki16425 significantly decreased both HB-EGF mRNA expression at the primary tumor site and circulating human HB-EGF concentrations in serum. All together our results demonstrate that HB-EGF is a new and relevant biomarker with potentially high value in quantifying LPA1 activation state in patients receiving anti-LPA1 therapies.