2012年8月31日 訊 /生物谷BIOON/ --美國俄亥俄州立大學(xué)綜合癌癥中心-阿瑟詹姆斯克腫瘤醫(yī)院和Richard J. Solove研究所的研究人員已經(jīng)發(fā)現(xiàn)乳腺癌細(xì)胞是如何抵抗他莫昔芬繼續(xù)生長和增殖的,。該研究也證實(shí)了一種新的試驗(yàn)性藥物可靶向治療他莫昔芬耐藥性乳腺癌。
刺猬(Hhg)信號(hào)轉(zhuǎn)導(dǎo)通路可以促進(jìn)他莫昔芬關(guān)閉雌激素激活途徑后乳腺癌細(xì)胞的生長,。第二條信號(hào)轉(zhuǎn)導(dǎo)通路PI3K/AKT也參與其中,。Hhg信號(hào)通路的激活使他莫昔芬治療無效，使腫瘤恢復(fù)增長和發(fā)展,。
作為這項(xiàng)研究的一部分,，研究人員分析了超過300例腫瘤樣本，發(fā)現(xiàn)Hhg信號(hào)激活的腫瘤患者預(yù)后更差,。最后,，研究人員發(fā)現(xiàn)在動(dòng)物模型中,，實(shí)驗(yàn)性藥物Vismodegib可阻止Hhg信號(hào)途徑，抑制他莫昔芬耐藥的人乳腺腫瘤的生長,。該藥物目前正在臨床試驗(yàn)中測試對(duì)其它類型癌癥的功效,。
目前，化療常用于治療耐激素的乳腺癌,，但這會(huì)帶來顯著副作用,。本研究發(fā)現(xiàn)的抗腫瘤的靶向治療藥物可能是一個(gè)替代化療手段的新的癌癥治療手段。這項(xiàng)研究發(fā)表在Cancer Research雜志上,。第一作者Bhuvaneswari Ramaswamy博士說：我們的研究結(jié)果表明,，我們可以針對(duì)他莫昔芬治療失敗的雌激素受體乳腺癌患者體內(nèi)的這條信號(hào)途徑來開展治療。
分子和細(xì)胞生物化學(xué)研究助理教授Sarmila Majumder說：我們著重描述了促進(jìn)他莫昔芬耐藥性的產(chǎn)生以及能激活PI3K/AKT通路的Hedgehog信號(hào)通路,。單獨(dú)靶向Hedgehog信號(hào)通路或聯(lián)合作用于Hedgehog信號(hào)通路和PI3K/AKT途徑可能是治療他莫昔芬耐藥性乳腺癌的一種新的治療選擇,。（生物谷：Bioon.com）
doi:10.1158/0008-5472.CAN-12-1248
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Hedgehog signaling is a novel therapeutic target in tamoxifen resistant breast cancer aberrantly activated by PI3K/AKT pathway
Bhuvaneswari Ramaswamy, Yuanzhi Lu, Kun-yu Teng, Gerard Nuovo, Xiaobai Li, Charles L Shapiro, and Sarmila Majumder,*
Endocrine resistance is a major challenge in the management of estrogen-receptor (ER) positive breast cancers. Although multiple mechanisms leading to endocrine resistance have been proposed, the poor outcome of patients developing resistance to endocrine therapy warrants additional studies. Here we show that non-canonical Hedgehog (Hhg) signaling is an alternative growth promoting mechanism that is activated in tamoxifen-resistant tumors. Importantly, PI3K/AKT pathway plays a key role in regulating Hhg signaling by protecting key components of this pathway from proteasomal degradation. The levels of Hhg signaling molecules SMO, GLI1 and the targets were significantly elevated in tamoxifen-resistant MCF-7 cells and T47D cells. Serial passage of the resistant cells in mice resulted in aggressive tumors that metastasized to distant organs with concurrent increases in Hhg marker expression and epithelial mesenchymal transition. RNAi-mediated depletion of SMO or GLI1 in the resistant cells resulted in reduced proliferation, clonogenic survival and delayed G1-S transition. Notably, treatment of resistant cells with PI3K inhibitors decreased SMO and GLI1 protein levels and activity that was rescued upon blocking GSK3β and proteasomal degradation. Furthermore, treatment of tamoxifen resistant xenografts with anti-Hhg compound GDC-0449 blocked tumor growth in mice. Importantly, high GLI1 expression correlated inversely with disease-free and overall survival in a cohort of 315 breast cancer patients. In summary, our results describe a signaling event linking PI3K/AKT pathway with Hhg signaling that promotes tamoxifen resistance. Targeting Hhg pathway alone or in combination with PI3K/AKT pathway could therefore be a novel therapeutic option in treating endocrine resistant breast cancer.
