Expression of CCL2/CCR2 signaling proteins in breast carcinoma cells is associated with invasive progression

• Published in: Scientific reports Vol. 11; no. 1; p. 8708
• Main Authors: Fang, Wei Bin, Sofia Acevedo, Diana, Smart, Curtis, Zinda, Brandon, Alissa, Nadia, Warren, Kyle, Fraga, Garth, Huang, Li-Ching, Shyr, Yu, Li, Wei, Xie, Lu, Staggs, Vincent, Hong, Yan, Behbod, Fariba, Cheng, Nikki
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22-04-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/67/1347; 631/67/1857; 631/67/395; 631/67/70; Animals; Breast cancer; Breast carcinoma; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Carcinoma, Ductal, Breast - metabolism; Carcinoma, Ductal, Breast - pathology; CCR2 protein; Chemokine CCL2 - metabolism; Chemokines; Disease Progression; Epithelial cells; Female; Heterografts; Humanities and Social Sciences; Humans; Inflammation; Invasiveness; Mice; Middle Aged; Monocyte chemoattractant protein 1; multidisciplinary; Neoplasm Invasiveness; Receptors, CCR2 - metabolism; Science; Science (multidisciplinary); Signal Transduction; Smad3 protein; Tumor cell lines
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-88229-0

Ductal carcinoma in situ (DCIS) is the most common type of pre-invasive breast cancer diagnosed in women. Because the majority of DCIS cases are unlikely to progress to invasive breast cancer, many women are over-treated for DCIS. By understanding the molecular basis of early stage breast cancer progression, we may identify better prognostic factors and design treatments tailored specifically to the predicted outcome of DCIS. Chemokines are small soluble molecules with complex roles in inflammation and cancer progression. Previously, we demonstrated that CCL2/CCR2 chemokine signaling in breast cancer cell lines regulated growth and invasion through p42/44MAPK and SMAD3 dependent mechanisms. Here, we sought to determine the clinical and functional relevance of CCL2/CCR2 signaling proteins to DCIS progression. Through immunostaining analysis of DCIS and IDC tissues, we show that expression of CCL2, CCR2, phospho-SMAD3 and phospho-p42/44MAPK correlate with IDC. Using PDX models and an immortalized hDCIS.01 breast epithelial cell line, we show that breast epithelial cells with high CCR2 and high CCL2 levels form invasive breast lesions that express phospho-SMAD3 and phospho-p42/44MAPK. These studies demonstrate that increased CCL2/CCR2 signaling in breast tissues is associated with DCIS progression, and could be a signature to predict the likelihood of DCIS progression to IDC.