Key signalling nodes in mammary gland development and cancer. The Snail1-Twist1 conspiracy in malignant breast cancer progression

Abstract

Breast cancer is the most common cancer among women, and despite significant advances in diagnosing and treating it, metastatic spread of cancer cells results in a high mortality rate. Epithelial-to-mesenchymal transition (EMT) is an embryonic program in which epithelial cells lose their characteristics and gain mesenchymal features. Therefore, EMT might play a very important role during malignant tumour progression. In this review we summarise recent advances in breast cancer research with a particular focus on the transcription factors Snail1 and Twist1. Besides discussing the role of EMT in normal mammary gland development, we describe regulatory mechanisms involving newly discovered upstream regulators and microRNAs, the association of EMT with breast cancer stem cells, and the involvement of the tumour microenvironment in breast cancer progression.

Figure 1

Role of Snail1 and Twist1 during mammary gland development and breast cancer progression. In females, release of ovarian hormones induces further development of the mammary gland. Snail1 and Snail2 control aromatase expression, indicating that they have a role in development of the ductal network. Somatic mutations and/or aberrant expression of oncogenes can cause proliferation of mammary epithelial cells. During malignant cancer progression, Snail1 induces an epithelial-to-mesenchymal transition (EMT) of epithelial breast cancer cells, which grants them invasive and migratory capacities. Twist1 plays a role in the development of distant metastasis by prompting cancer cells to enter the bloodstream. At distant organs, these cells undergo a mesenchymal-to-epithelial transition (MET).

Figure 2

Snail1 and Twist1 contribute to a series of normal processes and cancer related progression in the mammary gland. Snail1 and Twist1 contribute to different developmental and pathological outcomes in the mammary gland. Several epithelial-to-mesenchymal transition (EMT)-inducing signals in breast epithelial cells induce Snail1 and Twist1 transcription factors. Examples of effector or direct target genes that are regulated by Snail1 and Twist1 to produce the indicated outcomes are shown. Note that in many cases numerous targets that mediate a specific outcome have been identified, but only one example target or effector gene is shown here. AKT2, v-akt murine thymoma viral oncogene homolog 2; CAR, coxsackie virus and adenovirus receptor; HIF-1α, hypoxia inducible factor-1 alpha; IL-6, interleukin-6; LBX1, ladybird homeobox 1; MiR- 10b, microRNA-10b; NF-κB, nuclear factor-κB; p21, cyclin dependent kinase inhibitor 1A; p16, cyclin dependent kinase inhibitor 2A; Src-1, steroid receptor co-activator-1; TGF-β, transforming growth factor-beta; TNF-α, tumour necrosis factor-alpha; TrkB, neutrophic tyrosine kinase receptor; Wnt, wingless-type MMTV integration site family; YB-1, Y-box binding protein 1; ZEB1, zinc finger E-box-binding homeobox.