Basal subtype breast cancers have a particularly poor prognosis, with high invasiveness and resistance to most targeted therapies. TGFβ and MYC drive central features of basal breast cancer: TGFβ is an autocrine and paracrine signaling factor that drives cell invasion and metastasis, and MYC is a central regulator of cellular proliferation that is upregulated in many cancer types. We show here that genetic or pharmacological inhibition of MYC in MCF10A basal breast cells results in increased sensitivity to TGFβ-stimulated invasion and metastasis, and also show that this signaling loop is dependent on activation of SRC. Analysis of human breast cancer datasets and additional experiments with breast cancer cell lines further suggest the relevance of this signaling loop in basal, but not luminal, breast cancers. Our results imply precaution should be taken when utilizing therapeutic inhibitors of MYC with basal breast cancer patients as this could lead to increased metastasis; however, simultaneous pharmacological inhibition of SRC and MYC for these patients could facilitate the anti-proliferative effects of MYC inhibition while blocking the consequent promotion of metastasis.

Highlights d The oncogenes, kRas V12 and cMYC, have differing impacts on epithelial mechanics d kRas V12 cells are hyper-contractile, generating anisotropic strain across tissue d Wild-type tissue responds to kRas V12 -induced strain by altering cell division d Relieving hyper-contractility restores isotropy and divisions and reduces tumor growth

Carcinomas dysregulate their microenvironment and this helps aid disease progression, in part by altering the behaviour of host cells from different lineages, such as immune and endothelial cells. However, it remains largely unknown whether small groups of cells with initial oncogenic changes alter their environment or affect fundamental processes, such as cell division, in host epithelia. In this study, clusters of oncogene-expressing cells were created within otherwise normal, in vivo tissue, using Xenopus embryos. We find that clusters overexpressing kRas V12 or cMYC significantly increase cell division in neighbouring host epithelium. Furthermore, we show that hyper-contractility of kRas V12 clusters generates forces that deform host epithelia, increasing cell division and biasing division orientation. Contrastingly, cMYC clusters do not induce deformation of surrounding tissue but drive host cell division via a distinct mechanism. Our results indicate novel roles for kRas V12 and cMYC, dysregulating cell division in surrounding host, as well as oncogeneexpressing, epithelium.