PAQR8 promotes breast cancer recurrence and confers resistance to multiple therapies.
PAQR8 promotes breast cancer recurrence and confers resistance to multiple therapies.
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DOI：
10.1186/s13058-022-01559-3
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发表时间：
2023-01-03
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影响因子：
--
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乳腺癌的死亡率主要是由于复发性疾病对治疗产生抗药性。我们最近发现，与乳腺癌患者的原发肿瘤相比，在复发性转移性肿瘤中优先发生的四种局灶性CN改变中，假定的膜孕酮受体PAQR8的拷贝数（CN）增加是其中之一。PAQR8是否在癌症中发挥功能性作用尚不清楚。值得注意的是，在接受抗雌激素治疗的患者中，复发肿瘤中PAQR8 CN的增加与激活ESR1突变相互排斥，并且在接受抗雌激素治疗的患者和接受化疗或抗her2药物治疗的患者中，有50%的患者发生PAQR8 CN的增加。我们使用原位小鼠模型来确定PAQR8过表达或缺失是否会改变乳腺癌治疗后的休眠或复发。体外研究，包括集落形成、细胞活力和相对细胞适应度的测定，用于鉴定PAQR8在治疗中的作用。细胞凋亡和增殖标志物免疫荧光染色定量测定细胞存活和增殖情况。采用液相色谱-高分辨质谱法定量测定鞘脂。我们发现PAQR8对于小鼠乳腺肿瘤的有效复发是必要和充分的，在多种小鼠模型中治疗后出现的复发肿瘤中自发上调和CN获得，并且与乳腺癌患者复发后的低生存率和低总生存率相关。在氟维司汀或雌激素剥夺抑制雌激素受体通路、拉帕替尼阻断Her2通路或下调Her2通路以及化疗药物治疗后，PAQR8通过提高肿瘤细胞存活来促进治疗耐药。PAQR8的促生存作用是通过Gi蛋白依赖性cAMP水平的降低介导的，不需要孕酮，并且涉及PAQR8依赖性神经酰胺水平的降低和鞘氨醇-1-磷酸水平的增加，这表明PAQR8可能具有神经酰胺酶活性。我们的数据提供了体内证据，证明PAQR8在癌症中发挥功能作用，暗示PAQR8、cAMP和神经酰胺代谢在乳腺癌复发中起作用，并确定了一种可能共同促进乳腺癌患者获得治疗耐药的新机制。在线版本包含补充材料，可在10.1186/s13058-022-01559-3获得。
Breast cancer mortality is principally due to recurrent disease that becomes resistant to therapy. We recently identified copy number (CN) gain of the putative membrane progesterone receptor PAQR8 as one of four focal CN alterations that preferentially occurred in recurrent metastatic tumors compared to primary tumors in breast cancer patients. Whether PAQR8 plays a functional role in cancer is unknown. Notably, PAQR8 CN gain in recurrent tumors was mutually exclusive with activating ESR1 mutations in patients treated with anti-estrogen therapies and occurred in > 50% of both patients treated with anti-estrogen therapies and those treated with chemotherapy or anti-Her2 agents. We used orthotopic mouse models to determine whether PAQR8 overexpression or deletion alters breast cancer dormancy or recurrence following therapy. In vitro studies, including assays for colony formation, cell viability, and relative cell fitness, were employed to identify effects of PAQR8 in the context of therapy. Cell survival and proliferation were quantified by immunofluorescence staining for markers of apoptosis and proliferation. Sphingolipids were quantified by liquid chromatography-high resolution mass spectrometry. We show that PAQR8 is necessary and sufficient for efficient mammary tumor recurrence in mice, spontaneously upregulated and CN gained in recurrent tumors that arise following therapy in multiple mouse models, and associated with poor survival following recurrence as well as poor overall survival in breast cancer patients. PAQR8 promoted resistance to therapy by enhancing tumor cell survival following estrogen receptor pathway inhibition by fulvestrant or estrogen deprivation, Her2 pathway blockade by lapatinib or Her2 downregulation, and treatment with chemotherapeutic agents. Pro-survival effects of PAQR8 were mediated by a Gi protein-dependent reduction in cAMP levels, did not require progesterone, and involved a PAQR8-dependent decrease in ceramide levels and increase in sphingosine-1-phosphate levels, suggesting that PAQR8 may possess ceramidase activity. Our data provide in vivo evidence that PAQR8 plays a functional role in cancer, implicate PAQR8, cAMP, and ceramide metabolism in breast cancer recurrence, and identify a novel mechanism that may commonly contribute to the acquisition of treatment resistance in breast cancer patients. The online version contains supplementary material available at 10.1186/s13058-022-01559-3.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
实现癌症基因组数据的共同愿景。
DOI：
10.1056/nejmp1607591
发表时间：
2016-09-22
期刊：
The New England journal of medicine
影响因子：
--
作者：
Grossman RL;Heath AP;Ferretti V;Varmus HE;Lowy DR;Kibbe WA;Staudt LM
通讯作者：
Staudt LM
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
DOI：
10.1158/1078-0432.ccr-13-2332
发表时间：
2014-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Jeselsohn R;Yelensky R;Buchwalter G;Frampton G;Meric-Bernstam F;Gonzalez-Angulo AM;Ferrer-Lozano J;Perez-Fidalgo JA;Cristofanilli M;Gómez H;Arteaga CL;Giltnane J;Balko JM;Cronin MT;Jarosz M;Sun J;Hawryluk M;Lipson D;Otto G;Ross JS;Dvir A;Soussan-Gutman L;Wolf I;Rubinek T;Gilmore L;Schnitt S;Come SE;Pusztai L;Stephens P;Brown M;Miller VA
通讯作者：
Miller VA
影响因子：
11.2
作者：
Alvarez JV;Belka GK;Pan TC;Chen CC;Blankemeyer E;Alavi A;Karp JS;Chodosh LA
通讯作者：
Chodosh LA