Effects of Tamoxifen and oestrogen on histology and radiographic density in high and low mammographic density human breast tissues maintained in murine tissue engineering chambers

Abstract

Mammographic density (MD) is a strong risk factor for breast cancer. It is altered by exogenous endocrine treatments, including hormone replacement therapy and Tamoxifen. Such agents also modify breast cancer (BC) risk. However, the biomolecular basis of how systemic endocrine therapy modifies MD and MD-associated BC risk is poorly understood. This study aims to determine whether our xenograft biochamber model can be used to study the effectiveness of therapies aimed at modulating MD, by examine the effects of Tamoxifen and oestrogen on histologic and radiographic changes in high and low MD tissues maintained within the biochamber model. High and low MD human tissues were precisely sampled under radiographic guidance from prophylactic mastectomy fresh specimens of high-risk women, then inserted into separate vascularized murine biochambers. The murine hosts were concurrently implanted with Tamoxifen, oestrogen or placebo pellets, and the high and low MD biochamber tissues maintained in the murine host environment for 3 months, before the high and low MD biochamber tissues were harvested for histologic and radiographic analyses. The radiographic density of high MD tissue maintained in murine biochambers was decreased in Tamoxifen-treated mice compared to oestrogen-treated mice (p = 0.02). Tamoxifen treatment of high MD tissue in SCID mice led to a decrease in stromal (p = 0.009), and an increase in adipose (p = 0.023) percent areas, compared to placebo-treated mice. No histologic or radiographic differences were observed in low MD biochamber tissue with any treatment. High MD biochamber tissues maintained in mice implanted with Tamoxifen, oestrogen or placebo pellets had dynamic and measurable histologic compositional and radiographic changes. This further validates the dynamic nature of the MD xenograft model, and suggests the biochamber model may be useful for assessing the underlying molecular pathways of Tamoxifen-reduced MD, and in testing of other pharmacologic interventions in a preclinical model of high MD.

Mammographic density: a potential monitoring biomarker for adjuvant and preventative breast cancer endocrine therapies

“…Therefore, it is worthwhile reviewing the established and possible mechanisms through which tamoxifen could impact both MD and BC. In terms of tamoxifen effects on breast tissue, the drug was noted to cause a reduction in the stromal component of biochamber-implanted HMD tissue, which was associated with reduction of MD [66]. In addition to contributing to an HMD status [67], a high stromal density contributes to a higher BC risk in animals [68, 69].…”

High mammographic density is associated with an increase in stromal collagen and immune cells within the mammary epithelium

“…Thus, it is likely that oestradiol and progesterone synergistically cause a transient rise in MD in the luteal phase [ 4 ]. We showed that MD of human breast tissue in our xenograft murine engineering chambers was influenced by the murine peripartum states as well as by tamoxifen treatment of the nonobese diabetic/severe combined immunodeficiency NOD SCID mice [ 75 , 76 ]. Our unique within-individual paired analyses eliminated confounders such as different stages of the menstrual cycle or menopausal status among women; however, we did not observe any significant difference in the percentage expression of ER and PR between HMD and LMD tissue within the same individual.…”

Breast density: why all the fuss?

“…Some groups have found increased stromal expression of ER and epithelial or stromal expression of PR in dense tissue samples from women at population risk or increased risk (80,81). Laboratory studies using mouse models and human tissue xenografts have shown that tamoxifen treatment promotes remodelling of stroma to a tumour-inhibitory phenotype, with reduced extracellular matrix turnover and decreased stromal tissue (82,83).…”