Department of Orthopaedic Surgery, Stanford University School of Medicine, 450 Broadway Street, Pavilion C, 4th Floor, Redwood City, CA, 94063-6342, USA.
Department of Biomedical Data Science, Stanford University School of Medicine, Redwood Building, Room T101F (MC 5405), Stanford, CA, 94305, USA.
Breast Cancer Res. 2017 Nov 15;19(1):121. doi: 10.1186/s13058-017-0910-x.
Approximately 70% of all breast cancers express the estrogen receptor, and are regulated by estrogen. While the ovaries are the primary source of estrogen in premenopausal women, most breast cancer is diagnosed following menopause, when systemic levels of this hormone decline. Estrogen production from androgen precursors is catalyzed by the aromatase enzyme. Although aromatase expression and local estrogen production in breast adipose tissue have been implicated in the development of primary breast cancer, the source of estrogen involved in the regulation of estrogen receptor-positive (ER+) metastatic breast cancer progression is less clear.
Bone is the most common distant site of breast cancer metastasis, particularly for ER+ breast cancers. We employed a co-culture model using trabecular bone tissues obtained from total hip replacement (THR) surgery specimens to study ER+ and estrogen receptor-negative (ER-) breast cancer cells within the human bone microenvironment. Luciferase-expressing ER+ (MCF-7, T-47D, ZR-75) and ER- (SK-BR-3, MDA-MB-231, MCF-10A) breast cancer cells were cultured directly on bone tissue fragments or in bone tissue-conditioned media, and monitored over time with bioluminescence imaging (BLI). Bone tissue-conditioned media were generated in the presence vs. absence of aromatase inhibitors, and testosterone. Bone tissue fragments were analyzed for aromatase expression by immunohistochemistry.
ER+ breast cancer cells were preferentially sustained in co-cultures with bone tissues and bone tissue-conditioned media relative to ER- cells. Bone fragments analyzed by immunohistochemistry revealed expression of the aromatase enzyme. Bone tissue-conditioned media generated in the presence of testosterone had increased estrogen levels and heightened capacity to stimulate ER+ breast cancer cell proliferation. Pretreatment of cultured bone tissues with aromatase inhibitors, which inhibited estrogen production, reduced the capacity of conditioned media to stimulate ER+ cell proliferation.
These results suggest that a local estrogen signaling axis regulates ER+ breast cancer cell viability and proliferation within the bone metastatic niche, and that aromatase inhibitors modulate this axis. Although endocrine therapies are highly effective in the treatment of ER+ breast cancer, resistance to these treatments reduces their efficacy. Characterization of estrogen signaling networks within the bone microenvironment will identify new strategies for combating metastatic progression and endocrine resistance.
约 70%的乳腺癌表达雌激素受体，受雌激素调控。在绝经前妇女中，卵巢是雌激素的主要来源，但大多数乳腺癌是在绝经后诊断的，此时这种激素的全身水平下降。雄激素前体向雌激素的转化由芳香酶催化。尽管乳腺脂肪组织中的芳香酶表达和局部雌激素产生与原发性乳腺癌的发生有关，但参与调节雌激素受体阳性（ER+）转移性乳腺癌进展的雌激素来源尚不清楚。
骨骼是乳腺癌转移最常见的远处部位，特别是对于 ER+乳腺癌。我们采用共培养模型，使用全髋关节置换（THR）手术标本获得的小梁骨组织，研究 ER+和雌激素受体阴性（ER-）乳腺癌细胞在人骨微环境中的情况。荧光素酶表达的 ER+（MCF-7、T-47D、ZR-75）和 ER-（SK-BR-3、MDA-MB-231、MCF-10A）乳腺癌细胞直接培养在骨组织碎片上或骨组织条件培养基中，并通过生物发光成像（BLI）随时间进行监测。在存在或不存在芳香酶抑制剂和睾丸酮的情况下生成骨组织条件培养基，并通过免疫组织化学分析骨组织中芳香酶的表达。
与 ER-细胞相比，ER+乳腺癌细胞在与骨组织和骨组织条件培养基的共培养中更优先维持。通过免疫组织化学分析的骨组织碎片显示出芳香酶酶的表达。在存在睾丸酮的情况下生成的骨组织条件培养基具有更高的雌激素水平和刺激 ER+乳腺癌细胞增殖的能力。用芳香酶抑制剂预处理培养的骨组织，抑制雌激素产生，降低了条件培养基刺激 ER+细胞增殖的能力。
这些结果表明，局部雌激素信号轴调节 ER+乳腺癌细胞在骨转移灶中的活力和增殖，而芳香酶抑制剂调节该轴。尽管内分泌治疗在 ER+乳腺癌的治疗中非常有效，但对这些治疗的耐药性降低了其疗效。对骨微环境中雌激素信号网络的特征分析将确定对抗转移性进展和内分泌耐药的新策略。
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