Abstract
BackgroundBreast carcinoma can be classified as either Estrogen Receptor (ER) positive or negative by immunohistochemical phenotyping, although ER expression may vary from 1 to 100% of malignant cells within an ER + tumor. This is similar to genetic variability observed in other tumor types and is generally viewed as a consequence of intratumoral evolution driven by random genetic mutations. Here we view cellular evolution within tumors as a classical Darwinian system in which variations in molecular properties represent predictable adaptations to spatially heterogeneous environmental selection forces. We hypothesize that ER expression is a successful adaptive strategy only if estrogen is present in the microenvironment. Since the dominant source of estrogen is blood flow, we hypothesized that, in general, intratumoral regions with higher blood flow would contain larger numbers of ER + cells when compared to areas of low blood flow and in turn necrosis.MethodsThis study used digital pathology whole slide image acquisition and advanced image analysis algorithms. We examined the spatial distribution of ER + and ER- cells, vascular density, vessel area, and tissue necrosis within histological sections of 24 breast cancer specimens. These data were correlated with the patients ER status and molecular pathology report findings.ResultsANOVA analyses revealed a strong correlation between vascular area and ER expression and between high fractional necrosis and absent ER expression (R2 = 39%; p < 0.003 and R2 = 46%; p < 0.001), respectively). ER expression did not correlate with tumor grade or size.ConclusionWe conclude that ER expression can be understood as a Darwinian process and linked to variations in estrogen delivery by temporal and spatial heterogeneity in blood flow. This correlation suggests strategies to promote intratumoral blood flow or a cyclic introduction of estrogen in the treatment schedule could be explored as a counter-intuitive approach to increase the efficacy of anti-estrogen drugs.
Highlights
Breast carcinoma can be classified as either Estrogen Receptor (ER) positive or negative by immunohistochemical phenotyping, ER expression may vary from 1 to 100% of malignant cells within an ER + tumor
Since the source of estrogen in the breast is typically interstitial fluid and moves from the vessels into the cell by a simple reaction diffusion model identical to oxygen, nutrients, etc. [19], we propose the hypothesis that ER + cells will be found in regions of high blood flow while ER- cells will be present in regions of poor blood flow
This results in the prediction that the prevalence of ER + cells will generally follow the distribution of blood flow. To test this hypothesis we examined regional distribution of ER + and ER- cells compared to vascular density and regional necrosis within 24 clinical breast cancers of variable ER status and tumor grade
Summary
Breast carcinoma can be classified as either Estrogen Receptor (ER) positive or negative by immunohistochemical phenotyping, ER expression may vary from 1 to 100% of malignant cells within an ER + tumor. This is similar to genetic variability observed in other tumor types and is generally viewed as a consequence of intratumoral evolution driven by random genetic mutations. We acknowledge that a large body of work exists which addresses the complex dynamics of ER expression in vitro [16,17] and in vivo (Shipitson et al [18]) We embrace these works and do not suggest that phenotypic adaptation alone is sufficient explain variation in ER expression
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