Abstract PD7-03: Investigating cortactin as a genetic driver of disease progression in invasive lobular carcinoma

Abstract

Abstract Invasive lobular carcinoma (ILC) is the second most common type of breast cancer following invasive ductal carcinoma (IDC) and accounts for 10-15% of all cases. Unlike the masses or lumps formed by IDCs, ILCs grow as small, dyscohesive cells in a single-file pattern within dense layers of extracellular matrix. Paradoxically, while patients with ILC display favorable prognostic and predictive factors (Estrogen Receptor [ER]+, Progesterone Receptor+, HER2-, low Ki67), they present with more frequent long-term recurrences compared to those with IDC, indicative of endocrine resistance. Thus, there is urgent need to investigate genetic drivers of ILC disease progression in order to develop more effective therapeutic strategies and improve patient outcome. To this end, we used the Nanostring platform to measure the expression of 577 copy number variation-associated genes in 131 primary ILC tumors with long-term clinical data. This analysis identified CTTN (Cortactin; cortical actin binding protein) as a candidate ILC driver that exhibited higher expression in tumors from patients with subsequent recurrent (n=33) versus non-current disease (n=98). We further validated high CTTN mRNA/protein expression in human ILC cell lines, tumors and patient-derived xenografts, and CTTN locus (11q13.3) amplification in clinical ILC metastases to the brain, bone and ovaries. In follow-upin vitro studies, RNAi-mediated inhibition of CTTN diminished the adhesion and haptotaxis of human ILC cell lines to Collagen I, as well as impairing their growth in 3D Collagen I culture. To assess the functional role of CTTN in ILC tumor growth and metastasis, we transplanted control and CTTN knockdown human ILC cell lines into the mammary fat pads and ducts of immuno-compromised mice and monitored disease progression via bioluminescence imaging. While CTTN inhibition did not lead to a substantial impact on measurable tumor burden, both CTTN shRNAs resulted in a significant survival benefit in the fat pad model. Ongoing work is aimed at pinpointing the underlying mechanisms of CTTN's role in mediating growth in 3D Collagen I culture in vitro and disease progression in vivo. Collectively, the results of these studies will advance our understanding of ILC disease mechanisms and serve as a pre-clinical basis for improving the clinical outcome of patients with this understudied subtype of breast cancer. Citation Format: Tasdemir N, Sikora MJ, Zhu L, Levine KM, Scott J, Basudan A, Sflomos G, Sreekumar S, Bossart EA, Elishaev E, Chandran UR, Tseng GC, Jankowitz RC, Dabbs DJ, McAuliffe PF, Brisken C, Davidson NE, Oesterreich S. Investigating cortactin as a genetic driver of disease progression in invasive lobular carcinoma [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD7-03.