Molecular and Cellular Changes in Breast Cancer and New Roles of lncRNAs in Breast Cancer Initiation and Progression.

Breast cancer is not just one disease but many variations on a theme, comprising a variety of molecular subtypes with distinct etiologies, cellular origins, treatment strategies, and prognoses. Like mRNAs and microRNAs (miRNAs), long noncoding RNAs (lncRNAs) differ dramatically in expression across breast cancer subtypes and can be used for classification. While there has been considerable emphasis on miRNAs, our knowledge is still in its infancy about the role of lncRNAs that comprise the majority of the mammalian transcriptome. In this chapter, we will review the critical functions that lncRNAs play in breast cancer development and metastatic progression. We will conclude with a discussion of current and future approaches for RNA-targeted therapeutic intervention.

c-Myc and Her2 cooperate to drive a stem-like phenotype with poor prognosis in breast cancer.

The HER2 (ERBB2) and MYC genes are commonly amplified in breast cancer, yet little is known about their molecular and clinical interaction. Using a novel chimeric mammary transgenic approach and in vitro models, we demonstrate markedly increased self-renewal and tumour-propagating capability of cells transformed with Her2 and c-Myc. Coexpression of both oncoproteins in cultured cells led to the activation of a c-Myc transcriptional signature and acquisition of a self-renewing phenotype independent of an epithelial-mesenchymal transition programme or regulation of conventional cancer stem cell markers. Instead, Her2 and c-Myc cooperated to induce the expression of lipoprotein lipase, which was required for proliferation and self-renewal in vitro. HER2 and MYC were frequently coamplified in breast cancer, associated with aggressive clinical behaviour and poor outcome. Lastly, we show that in HER2(+) breast cancer patients receiving adjuvant chemotherapy (but not targeted anti-Her2 therapy), MYC amplification is associated with a poor outcome. These findings demonstrate the importance of molecular and cellular context in oncogenic transformation and acquisition of a malignant stem-like phenotype and have diagnostic and therapeutic consequences for the clinical management of HER2(+) breast cancer.

Characterization of mammary tumors from Brg1 heterozygous mice.

Mammalian SWI/SNF-related complexes have been implicated in cancer based on some of the subunits physically interacting with retinoblastoma (RB) and other proteins involved in carcinogenesis. Additionally, several subunits are mutated or not expressed in tumor-derived cell lines. Strong evidence for a role in tumorigenesis in vivo, however, has been limited to SNF5 mutations that result primarily in malignant rhabdoid tumors (MRTs) in humans and MRTs as well as other sarcomas in mice. We previously generated a null mutation of the Brg1 catalytic subunit in the mouse and reported that homozygotes die during embryogenesis. Here, we demonstrate that Brg1 heterozygotes are susceptible to mammary tumors that are fundamentally different than Snf5 tumors. First, mammary tumors are carcinomas not sarcomas. Second, Brg1+/- tumors arise because of haploinsufficiency rather than loss of heterozygosity. Third, Brg1+/- tumors exhibit genomic instability but not polyploidy based on array comparative genomic hybridization results. We monitored Brg1+/-, Brm-/- double-mutant mice but did not observe any tumors resembling those from Snf5 mutants, indicating that the Brg1+/- and Snf5+/- tumor phenotypes do not differ simply because Brg1 has a closely related paralog whereas Snf5 does not. These findings demonstrate that BRG1 and SNF5 are not functionally equivalent but protect against cancer in different ways. We also demonstrate that Brg1+/- mammary tumors have relatively heterogeneous gene expression profiles with similarities and differences compared to other mouse models of breast cancer. The Brg1+/- expression profiles are not particularly similar to mammary tumors from Wap-T121 transgenic line where RB is perturbed. We were also unable to detect a genetic interaction between the Brg1+/- and Rb+/- tumor phenotypes. These latter findings do not support a BRG1-RB interaction in vivo.