Inhibition Of The Tgf-Beta Pathway Enhances The Tumoricidal Effect Of Doxorubicin On Breast Cancer Cells

Triple negative breast cancer (TNBC) accounts for approximately 15% of all breast cancers but disproportionately accounts for the majority of breast cancer related deaths. As no specific signaling pathways driving TNBC growth have been established, chemotherapy with anthracycline drugs remains a mainstay of treatment. Although effective against TNBC, anthracyclines are known to cause dose limiting cardiac toxicity. We have previously shown that cardiovascular side effects of an anthracycline drug doxorubicin are mediated, at least in part, by the TGF-beta pathway. Therefore, we set out to determine if the TGF-beta signaling is upregulated in TNBC tissues, and suppression of this pathway impedes growth of TNBC cells. Using a database of 51 patients, we found that TNBC tumor samples were enriched for the TGF-beta pathway related transcripts, as compared to normal breast tissues. Furthermore, upregulated TGF-beta pathway related transcripts positively correlated with poor outcomes and, specifically, decreased survival of patients with TNBC. After this bioinformatic approach demonstrated a link between the TGF-beta pathway and TNBC progression, we assessed the effects of an ALK4/5/7 receptor kinase inhibitor SB431542, a known suppressor of the TGF-beta/Smad2/3 pathway, on proliferation and viability of cultured MDA-MB-231cells. Although effects of SB431542 alone were modest in this TNBC model system, its combination with an anthracycline drug doxorubicin more effectively suppressed viability of cultured breast cancer cells than either of these agents given alone. It appears that the enhanced tumoricidal effect of this drug combination was due to suppression of proliferation of MDA-MB-231 cells and not due to augmented apoptosis. Thus, the bioinformatic analysis of patients’ TNBC tissues transcriptome highlighted the role of the TGF-beta pathway in cancer progression. Complementing the doxorubicin treatment of the cultured TNBC model cells with an inhibitor of the TGF-beta pathway enhanced the tumoricidal effect of chemotherapy.