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.

<p>Legends for Supplemental Figures S1-S5.</p>

<p>Responsiveness of different molecular subtypes breast cancer cell lines to TGFβ as measured by PAI-1 expression levels (S1); TGFβ�and MYC knockdown inhibit cell proliferation (S2); MYC reduction potentiates TGFβ induced invasive phenotype in SUM149 cells (S3); Pharmacological inhibition of SRC blocks the effect of TGFβ treatment on increased levels of integrin αvβ3 (S4); Pharmacological inhibition of MYC mimics the effect of MYC knockdown on integrin αvβ3 levels, in a dose dependent manner (S5).</p>

<p>Legends for Supplemental Figures S1-S5.</p>

<p>Responsiveness of different molecular subtypes breast cancer cell lines to TGFβ as measured by PAI-1 expression levels (S1); TGFβ�and MYC knockdown inhibit cell proliferation (S2); MYC reduction potentiates TGFβ induced invasive phenotype in SUM149 cells (S3); Pharmacological inhibition of SRC blocks the effect of TGFβ treatment on increased levels of integrin αvβ3 (S4); Pharmacological inhibition of MYC mimics the effect of MYC knockdown on integrin αvβ3 levels, in a dose dependent manner (S5).</p>