The Hedgehog Pathway in Triple Negative Breast Cancer

Abstract

Triple negative breast cancer (TNBC) is a common subtype of breast cancer comprising about 15% of the 230,000 new breast cancer cases every year. TNBC is named due to the lack of three common receptors that are prevalent in most breast cancer: Estrogen Receptorα (ERα), Progesterone Receptor (PR), and Human Epidermal Growth Factor Receptor (HER2). Many breast tumors are induced through estrogen and ERα, but these can be treated with endocrine therapy which inhibits ERα. The lack of ERα and the other receptors limit drug options to chemotherapy regiments which tumors often develop resistance against. Consequently, it is important to identify new pathways involved in TNBC and drugs that can provide therapy to these patients. One such pathway is the Hedgehog (Hhg) pathway which is upregulated in a number of cancers like basal cell carcinoma and medulloblastoma. The Hhg pathway is a highly conserved pathway that is important for embryonic development and in controlling cell proliferation and differentiation. Due to the Hhg pathway’s selective activation in adult cancer cells, it is an ideal candidate for therapeutic intervention. We believe that the Hhg pathway plays an important role in TNBC development and can be targeted therapeutically in these patients. Here we show that in primary human breast tumors and in TNBC cell lines MDA-MB231, MDA-MB468, and BT20 that the Hhg pathway is activated and that it may be regulated in part through the PI3K/AKT pathway. We also show that the very promising anti-Hedgehog compound GDC-0449, already approved for basal cell carcinomas, can inhibit TNBC cell growth in combination with PI3K inhibitor. We intend to test the efficacy of GDC-0449 in combination with PI3K inhibitors in vivo to provide a novel targeted therapy for TNBC patients.