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P1 6 th <strong>International</strong> <strong>Workshop</strong> on Breast Densitometry and Breast Cancer Risk Assessment EXPLORING A RELATIONSHIP BETWEEN EXTRACELLULAR MATRIX STIFFNESS AND MAMMOGRAPHIC DENSITY IN THE HUMAN BREAST Irene Acerbi 1,2 , Alfred Au 2 , Ori Maller 1,2 , Quanming Shi 2,3 , Jan Liphardt 2,3 , Yunn-yi Chen 4 , Shelley Hwang 5 , Valerie M. Weaver 1,2,6,7,8 1 Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, CA, USA; 2 Bay Area Physical Sciences in Oncology Center, Berkeley, CA, USA 3 Department of Physics, University of California, Berkeley, CA, USA; 4 UCSF Carol Buck Breast Cancer Center, San Francisco, CA, USA; 5 Department of Pathology, University of California, San Francisco, CA, USA; 6 Department of Surgery, Duke University, Durham, NC, USA; 7 Institute for Regeneration Medicine, University of California San Francisco, CA, USA; 8 Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA; 9 Department of Anatomy, University of California, San Francisco, CA, USA Mammographic density (MD) is associated with high collagen content in the extracellular matrix (ECM) and greater risk to malignancy. Data from our group and others have highlighted the importance of mechanical cues from the ECM in breast tissue homeostasis and tumor progression [Paszek et al., Cancer Cell 2005; Levental et al., Cell, 2009; reviewed in Yu et al., Trends Cell Biol, 2010]. Nevertheless, a role for ECM stiffness in tumor cell initiation is unknown. In this study, we hypothesize that high MD correlates with stiffer breast ECM and enhances women’s risk for breast cancer compared to low MD. To test this hypothesis, we studied breast tissues obtained through prophylactic mastectomy from women with high MD (BIRADS 4) versus low (BIRADS 1). From each surgically excised breast, samples of 0.5cm x 0.5cm x 1cm dimension were removed from the retroareolar region and from 4 peripheral quadrants. Sample sections were subjected to biophysical, morphological and biochemical analysis. Biophysical analysis included the application of Atomic Force Microscopy (AFM) to obtain an extensive force map of distinct anatomical regions of the ECM associated with the intra-lobular and interlobular ECM. ECM architecture has been analyzed using two photons and SIM-POL imaging coupled with picrosirius staining, polarized light imaging and image quantification. Biochemical and morphological analysis consisted of immunohistochemistry for markers that detect mechano-signaling in the epithelium and stromal fibroblasts, and H&E to visualize cellular and ECM organization. We studied samples from the different 5 quadrants of a same breast. We found that the ECM associated with the upper outer region, was in tendency stiffer (AFM) and had higher tension (SIMPOL birefringence) than the other peripheral quadrants. We show heterogeneity within multiple regions of the same breast, with the upper outer region, where most tumors occur, contained linearized collagen fibrils. Most invasive breast cancers arise from the ductal epithelium. Therefore, we studied the ECM associated with the Terminal Ductal Lobular Units (TDLU): inter-lobular ECM (among the TLDU), and intra-lobular ECM (within the TDLU). The inter-lobular ECM of the breast contained linearized collagen fibrils and was relatively stiffer. In contrast, we found that the intra-lobular ECM associated with the TDLU in the breast contained less linearized collagen fibrils and was compliant. In a small cohort, breast tissues from of the upper outer region were examine to directly explore the relationship between extracellular matrix stiffness and high MD across a patient population. Our preliminary data suggest an increase in collagen abundance and higher content of linearized collagen fibers adjacent to TLDUs were associated with high MD. Our future efforts will focus on increasing the size of the cohort to further establish a correlative relationship between MD and ECM stiffness. We will also examine the significance of this relationship in tumor cell initiation. ABSTRACTS Acknowledgements: supported by W81XWH-05-1-0330 and R01 CA138818-01A1 to VMW, 1U01 ES019458-01 to VMW and ZW, and P50 CA 58207 to JG, VW, SH and LC, U54CA143836-01 to JL and VW, and Susan G. Komen for the Cure PSF12230246 to IA. 30
6 th <strong>International</strong> <strong>Workshop</strong> on Breast Densitometry and Breast Cancer Risk Assessment P2 COMPARISON OF BREAST DENSITY MEASUREMENTS WITH A MAMMOGRAPHIC VOLUMETRIC AND AREA ALGORITHM AND MAGNETIC RESONANCE IMAGING O Alonzo-Proulx 1 , J Mainprize 1 , E. Warner 1 , J. Harvey 2 , M. Yaffe 1 1 Sunnybrook Health Sciences Centre, 2075 Bayview Ave., Toronto, Ontario Canada, M4N 3M5 ; 2 University of Virginia Health System, Charlottesville, Virginia Introduction: Area and volumetric breast density (ABD and VBD) is typically determined from twodimensional x-ray projection mammograms. In this study we compare the values of ABD, VBD, dense volume and total breast volume estimated in this way, with measurements obtained directly from a threedimensional breast MRI image dataset. ABSTRACTS Materials and Methods: Our VBD algorithm, CUMULUS V, has been described earlier [1,2]. A calibration surface relating the imaging signal to the composition and thickness of breast phantoms is obtained experimentally, and corrected using simulation to compensate for the attenuation difference between the phantom materials and breast tissue. The response of the thickness readout of the mammography machine is characterized to allow for an accurate estimate of the breast thickness under compression. The ABD measurements were done using the CUMULUS area algorithm. The MR images were obtained from a study of high-risk women [3]. The images were segmented in four steps. 1) the inhomogeneities arising from the coil sensitivity were corrected semi-automatically in each slice; 2) a user delineated the chest wall and air boundaries; 3) a user manually selected the signal peaks due to fatty and fibroglandular tissue; 4) a soft-threshold function was applied between the peaks to transform the image into fractional density content. Images from 80 patients (left and right breast) were analyzed in this study. Results: The digital mammograms were obtained, on average, 3 years after the MR exam, when the mean age of the women was 45 years. Figure 1 and Table 1 compare the mammography and MR measurements. The mean VBD and volumes were 32.3 % and 677 cm 3 , respectively, for the mammography measurement versus 32.3 % and 645 cm 3 for the MR measurement. The comparison with ABD has not been completed at this point. Figure 1: comparison between the mammographic density algorithm and MRI for the VBD (left) and breast volume (right). 31
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