Role of Hs00 gene expression in recurrence mechanisms of human triple negative breast cancer Chiu JH1, Hsu CY2, Tsai YF1, Liu CY3, Huang TT3, Tseng LM1, Shyr YM1 Comprehensive Breast Health Center, Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taiwan, ROC 2. Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taiwan, ROC 3. Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.

Breast Cancer Therapies 1st cancer incidence / 3rd cause of cancer death in Taiwan female. 2017 Therapies surgery chemotherapy radiotherapy target therapy endocrinal therapy

Different Breast cancer subtypes 40% endocrinal therapy 20% chemotherapy /endocrinal therapy / target therapy Chemotherapy / target therapy 10-15% 在乳癌的分類中，有一種依據有無ER, PR, HER2表現有無可分為luminal A, luminal B, HER2, Triple negative 四種subtype 。若乳癌細胞含越多荷爾蒙受體像是luminal A,B type，其治療效果越好，預後越佳，另一個危險因子為人類表皮生長因子受體(HER 2)，此受體會加速癌細胞分裂，增加轉移，造成抗藥性。而Basal-like subtype此種subtype在免疫染色上為ER.PR-, HER2-，其預後差且易早期轉移。右方的圖顯示四種subtype的存活率，可發現紅色者為basal like，其存活率最低 ，最大原因是其對化療的反應不好，容易在早期就轉移 15-20% Chemotherapy ER: estrogen receptor, PR: progesterone receptor, HER2: human epidermal growth receptor 2 3 3

Triple Negative Breast Cancer Luminal A Luminal B HER2 Triple negative Probability 在乳癌的分類中，有一種依據有無ER, PR, HER2表現有無可分為luminal A, luminal B, HER2, Triple negative 四種subtype 。若乳癌細胞含越多荷爾蒙受體像是luminal A,B type，其治療效果越好，預後越佳，另一個危險因子為人類表皮生長因子受體(HER 2)，此受體會加速癌細胞分裂，增加轉移，造成抗藥性。而Basal-like subtype此種subtype在免疫染色上為ER.PR-, HER2-，其預後差且易早期轉移。右方的圖顯示四種subtype的存活率，可發現紅色者為basal like，其存活率最低 ，最大原因是其對化療的反應不好，容易在早期就轉移 Overall survival (months) 4 4

Subtypes of Triple Negative Breast Cancer Non-Asian Taiwanese Basal-like 1 Basal-like 2 Immune modulatory Mesenchymal Mesenchymal stem like Luminal androgen receptor Lehmann BD. JCI 2011 Tseng LM, BCRT 2017

Treatment of Triple Negative Breast Cancer ER (-), PR (-), HER2 (-), more aggressive, higher recurrence rate, chemo-sensitive or chemo-resistance? Emerging solutions anti-VEGF/VEGFR monoclonal antibodies anti-EGFR therapies mTOR inhibitors Other targets ? 三陰性乳癌占現行乳癌的15-20%的比例，特徵是常發生於年輕婦女身上，會形成較大的tumor等等 剛才提到，化療目前是三陰性乳癌的唯一治療選擇，那他的第一線用藥有Doxorubicin, Paclitaxel和Platinum agents， 但從治療後存活率可以看到，相較於其他乳癌subtypes，三陰性乳癌的治療成效明顯低上許多，這可能跟他容易產生chemo-resistance和metastasis有關 那為了提高三陰性乳癌的治療成效，陸續有新的標靶藥物策略出來 像是block住VEGF, EGFR, mTOR等等跟細胞生長相關的factor, receptor, pathway等等 但是有這麼多的研究結果出來，其實更表明了三陰性乳癌的臨床治療還沒有一個很好的guideline可以被follow 所以，有沒有其他的治療方式，例如中藥，可以改善三陰性乳癌的化療成效呢?

Our Strategy Tsai YF, Plos one, 2017

OpenArray plate technology Hydrophobic Hydrophilic 26880 RT-PCR Hs00 gene

Rationale: Aim of study: TNBC Hs00 gene Recurrence Hs00 gene Aim of study: The aim of this study was to investigate the role of Hs00 in recurrent mechanisms in TNBC cells.

results

Q: role of Hs00 on cell growth in MDA-MB-231/468 cells? results Q: role of Hs00 on cell growth in MDA-MB-231/468 cells?

results Cytosol Nuclear

Q: role of Hs00 on in vivo tumor growth and cell migration ? results Q: role of Hs00 on in vivo tumor growth and cell migration ?

Q: over-expressed Hs00 on TNBC cells? results Q: over-expressed Hs00 on TNBC cells? WT scramble o/e Hs00 No effect on cell growth

Q: Ingenuity Pathway Analysis for Hs00-related genes? results Q: Ingenuity Pathway Analysis for Hs00-related genes? Δ Hs00 o/e Hs00 * * * * *

DAPI Hs00 EGFR MERGE MDA-MB-231 MDA-MB-468 DAPI Hs00 EGFR MERGE

Small molecule inhibitors as targeted therapy Discussion Small molecule inhibitors as targeted therapy

Conclusion We conclude that Hs00 gene signaling plays an important role in recurrence mechanisms of TNBC patients, which provides a potential therapeutic target for treatment of TNBC.

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