Gene expression signature of normal cell-of-origin predicts ovarian tumor outcomes.

The potential role of the cell-of-origin in determining the tumor phenotype has been raised, but not adequately examined. We hypothesized that distinct cells-of-origin may play a role in determining ovarian tumor phenotype and outcome. Here we describe a new cell culture medium for in vitro culture of paired normal human ovarian (OV) and fallopian tube (FT) epithelial cells from donors without cancer. While these cells have been cultured individually for short periods of time, to our knowledge this is the first long-term culture of both cell types from the same donors. Through analysis of the gene expression profiles of the cultured OV/FT cells we identified a normal cell-of-origin gene signature that classified primary ovarian cancers into OV-like and FT-like subgroups; this classification correlated with significant differences in clinical outcomes. The identification of a prognostically significant gene expression signature derived solely from normal untransformed cells is consistent with the hypothesis that the normal cell-of-origin may be a source of ovarian tumor heterogeneity and the associated differences in tumor outcome.

The silent estrogen receptor--can we make it speak?

One of the most common cancers in women world wide, breast cancer is classically an endocrine-dependent cancer. It has been known for over a century that development, progression and metastasis of breast cancer are strongly influenced by hormonal factors. Indeed about two-thirds of breast cancers express the estrogen receptor α (ERα) protein, a key predictor of prognosis and response to endocrine therapy. These cancers are frequently amenable to therapies that target estrogen signaling pathways, including selective estrogen receptor modulators like tamoxifen, selective estrogen receptor downregulators like fulvestrant; and agents that reduce estrogen ligand like aromatase inhibitors and ovarian suppression through luteinizing hormone-releasing hormone (LHRH) agonists. It is likely that these approaches, especially adjuvant tamoxifen, have contributed to the reduction in breast cancer mortality that has been observed in recent years. However, data from clinical studies have suggested that only about 60% of ERα-positive breast cancers respond to hormonal therapy. Further, those tumors that lack expression of ERα and the estrogen-regulated progesterone receptor (PgR) are unresponsive to hormone therapy. Thus the problem of acquired or de novo endocrine resistance is a substantial one. Recent molecular and biological advances have contributed to our understanding about potential underlying mechanisms. Here we will focus especially on silencing the expression of ERα as one such endocrine-resistance mechanism and how it might be exploited clinically.

Functional proteomics approach to investigate the biological activities of cDNAs implicated in breast cancer.

Functional proteomics approaches that comprehensively evaluate the biological activities of human cDNAs may provide novel insights into disease pathogenesis. To systematically investigate the functional activity of cDNAs that have been implicated in breast carcinogenesis, we generated a collection of cDNAs relevant to breast cancer, the Breast Cancer 1000 (BC1000), and conducted screens to identify proteins that induce phenotypic changes that resemble events which occur during tumor initiation and progression. Genes were selected for this set using bioinformatics and data mining tools that identify genes associated with breast cancer. Greater than 1000 cDNAs were assembled and sequence verified with high-throughput recombination-based cloning. To our knowledge, the BC1000 represents the first publicly available sequence-validated human disease gene collection. The functional activity of a subset of the BC1000 collection was evaluated in cell-based assays that monitor changes in cell proliferation, migration, and morphogenesis in MCF-10A mammary epithelial cells expressing a variant of ErbB2 that can be inducibly activated through dimerization. Using this approach, we identified many cDNAs, encoding diverse classes of cellular proteins, that displayed activity in one or more of the assays, thus providing insights into a large set of cellular proteins capable of inducing functional alterations associated with breast cancer development.