Abstract
Hedgehog-Gli (Hh-Gli) signaling pathway is one of the new molecular targets found upregulated in breast tumors. Estrogen receptor alpha (ERα) signaling has a key role in the development of hormone-dependent breast cancer. We aimed to investigate the effects of inhibiting both pathways simultaneously on breast cancer cell survival and the potential interactions between these two signaling pathways. ER-positive MCF-7 cells show decreased viability after treatment with cyclopamine, a Hh-Gli pathway inhibitor, as well as after tamoxifen (an ERα inhibitor) treatment. Simultaneous treatment with cyclopamine and tamoxifen on the other hand, causes short-term survival of cells, and increased migration. We found upregulated Hh-Gli signaling under these conditions and protein profiling revealed increased expression of proteins involved in cell proliferation and migration. Therefore, even though Hh-Gli signaling seems to be a good potential target for breast cancer therapy, caution must be advised, especially when combining therapies. In addition, we also show a potential direct interaction between the Shh protein and ERα in MCF-7 cells. Our data suggest that the Shh protein is able to activate ERα independently of the canonical Hh-Gli signaling pathway. Therefore, this may present an additional boost for ER-positive cells that express Shh, even in the absence of estrogen.
Highlights
Breast cancer is a heterogeneous disease divided into three major subtypes with differing response to therapy: the hormone receptor-positive (with either estrogen receptor (ER) or progesterone receptor (PR) expression), the HER-2 amplified, and the triple-negative cancer (ER-negative, PR-negative and HER2-negative)
Combined treatments were with either cyclopamine for 48 h followed by tamoxifen for 48 h, tamoxifen for 48 h followed by cyclopamine for 48 h, cyclopamine + tamoxifen simultaneously for 48 h, cyclopamine + tamoxifen simultaneously for 96 h
To determine the effects of a combined treatment on cell proliferation, cells were treated with cyclopamine and tamoxifen in four different combinations: cyclopamine for 48 h followed by tamoxifen for 48 h, tamoxifen for 48 h followed by cyclopamine for 48 h, cyclopamine + tamoxifen simultaneously for 48 h and 96 h (Fig. 2E, F)
Summary
Breast cancer is a heterogeneous disease divided into three major subtypes with differing response to therapy: the hormone receptor-positive (with either estrogen receptor (ER) or progesterone receptor (PR) expression), the HER-2 amplified, and the triple-negative cancer (ER-negative, PR-negative and HER2-negative). For ER-positive tumors, therapy is mostly based on inhibition of estrogen synthesis or inhibition of estrogen receptor activity, for example tamoxifen is commonly used. The Hedgehog-Gli (Hh-Gli) signaling pathway is involved in embryonic development of mammary buds [2], and the pathway genes are expressed in the mammary gland during postnatal development [3]. The pathway is initiated with binding of the ligand Hedgehog (Sonic, Indian or Desert Hh) to its transmembrane receptor Patched (Ptch). Ptch relieves its repression of Smoothened (Smo), causing a phosphorylation cascade and the release of transcription factor Gli from Suppressor of Fused (SuFu). Gli translocates to the nucleus, where it initiates target gene transcription. Hh-Gli pathway target genes are involved in proliferation and differentiation, cell survival, self-renewal, angiogenesis, and pathway autoregulation [4,5,6]
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