Abstract
BackgroundApproximately 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.MethodsBone 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.ResultsER+ 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.ConclusionsThese 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.
Highlights
70% of all breast cancers express the estrogen receptor, and are regulated by estrogen
Tissues from male patients were collected because our initial observations, generated during another line of experimentation, revealed that estrogen receptor (ER)+ breast cancer cells were preferentially sustained in tissues from male and female patients
A b c demonstrated significantly greater bioluminescence imaging (BLI) signal for culture on bone vs. plastic for MCF-7 cells (p = 0.0053; 95% CI (0.1881 to 0.8424)), whereas BLI signal was significantly reduced for SK-BR-3 and MDA-MB-231 cells (p = .0184; 95% CI (−0.3807 to −0.04318)) and (p = 0.0003; 95% CI (−0.9934 to −0.4184)), respectively. These results suggest that the human bone tissue microenvironment of the female and male skeleton preferentially sustains the viability of ER+ breast cancer cells compared to ERbreast cancer cells seeded directly onto human bone tissue fragments
Summary
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. 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. While the ovaries are the primary source of estrogens in premenopausal women, most breast cancers are diagnosed during the postmenopausal years, when the ovaries no longer provide significant systemic levels of this hormone [6]. The largest source of estrogen is adipose tissue [4], and local production by breast adipose tissue has been linked to the development of primary breast cancer [7,8,9,10,11]. Estrogens are produced in a variety of other tissues, including the brain, vasculature smooth muscle, and bone, where they act locally in paracrine fashion [5]
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