The bone microenvironment increases phenotypic plasticity of ER+ breast cancer cells

被引：85

作者：

Bado, Igor L. ^{[1
,2
,3
]}

Zhang, Weijie ^{[1
,2
,3
]}

Hu, Jingyuan ^{[4
,5
,6
]}

Xu, Zhan ^{[1
,2
,3
]}

Wang, Hai ^{[1
,2
,3
]}

Sarkar, Poonam ^{[5
]}

Li, Lucian ^{[5
,6
]}

Wan, Ying-Wooi ^{[5
,6
,7
]}

Liu, Jun ^{[1
,2
,3
]}

Wu, William ^{[7
]}

Lo, Hin Ching ^{[1
,2
,3
]}

Kim, Ik Sun ^{[1
,2
,3
]}

Singh, Swarnima ^{[2
,3
]}

Janghorban, Mahnaz ^{[2
,3
]}

Muscarella, Aaron M. ^{[1
,2
,3
]}

Goldstein, Amit ^{[1
,2
,3
]}

Singh, Purba ^{[1
,2
,3
]}

Jeong, Hyun-Hwan ^{[8
]}

Liu, Chaozhong ^{[5
,6
]}

Schiff, Rachel ^{[1
,2
]}

Huang, Shixia ^{[3
]}

Ellis, Matthew J. ^{[1
,2
,3
]}

Gaber, M. Waleed ^{[5
]}

Gugala, Zbigniew ^{[9
]}

Liu, Zhandong ^{[6
,7
]}

Zhang, Xiang H-F ^{[1
,2
,3
,10
]}

机构：

[1] Baylor Coll Med, Lester & Sue Smith Breast Ctr, One Baylor Plaza, Houston, TX 77030 USA

[2] Baylor Coll Med, Dan L Duncan Canc Ctr, One Baylor Plaza, Houston, TX 77030 USA

[3] Baylor Coll Med, Dept Mol & Cellular Biol, One Baylor Plaza, Houston, TX 77030 USA

[4] Baylor Coll Med, Program Quantitat & Computat Biosci, One Baylor Plaza, Houston, TX 77030 USA

[5] Baylor Coll Med, Dept Pediat, One Baylor Plaza, Houston, TX 77030 USA

[6] Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA

[7] Baylor Coll Med, Dept Mol & Human Genet, One Baylor Plaza, Houston, TX 77030 USA

[8] Univ Texas Hlth Sci Ctr Houston, Ctr Precis Hlth, Sch Biomed Informat, Houston, TX 77030 USA

[9] Univ Texas Med Branch, Dept Orthoped Surg & Rehabil, 301 Univ Blvd, Galveston, TX 77555 USA

[10] Baylor Coll Med, McNair Med Inst, BCM600,One Baylor Plaza, Houston, TX 77030 USA

来源：

DEVELOPMENTAL CELL | 2021年 / 56卷 / 08期

关键词：

MAMMARY STEM-CELLS; GROUP PROTEIN EZH2; ESTROGEN-RECEPTOR; ENDOCRINE-THERAPY; OSTEOGENIC NICHE; METASTASIS; TUMOR; EXPRESSION; GROWTH; PROGRESSION;

D O I：

10.1016/j.devcel.2021.03.008

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Estrogen receptor-positive (ER+) breast cancer exhibits a strong bone tropism in metastasis. How the bone microenvironment (BME) impacts ER signaling and endocrine therapy remains poorly understood. Here, we discover that the osteogenic niche transiently and reversibly reduces ER expression and activities specifically in bone micrometastases (BMMs), leading to endocrine resistance. As BMMs progress, the ER reduction and endocrine resistance may partially recover in cancer cells away from the osteogenic niche, creating phenotypic heterogeneity in macrometastases. Using multiple approaches, including an evolving barcoding strategy, we demonstrated that this process is independent of clonal selection, and represents an EZH(2)-mediated epigenomic reprogramming. EZH2 drives ER+ BMMs toward a basal and stem-like state. EZH2 inhibition reverses endocrine resistance. These data exemplify how epigenomic adaptation to BME promotes phenotypic plasticity of metastatic seeds, fosters intra-metastatic heterogeneity, and alters therapeutic responses. Our study provides insights into the clinical enigma of ER+ metastatic recurrences despite endocrine therapies.

引用

页码：1100 / +

页数：27

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