Abstract
Human surfactant protein D (SP-D) belongs to the family of collectins that is composed of a characteristic amino-terminal collagenous region and a carboxy-terminal C-type lectin domain. Being present at the mucosal surfaces, SP-D acts as a potent innate immune molecule and offers protection against non-self and altered self, such as pathogens, allergens, and tumor. Here, we examined the effect of a recombinant fragment of human SP-D (rfhSP-D) on a range of breast cancer lines. Breast cancer has four molecular subtypes characterized by varied expressions of estrogen (ER), progesterone (PR), and epidermal growth factor (EGF) receptors (HER2). The cell viability of HER2-overexpressing (SKBR3) and triple-positive (BT474) breast cancer cell lines [but not of a triple-negative cell line (BT20)] was reduced following rfhSP-D treatment at 24 h. Upregulation of p21/p27 cell cycle inhibitors and p53 phosphorylation (Ser15) in rfhSP-D-treated BT474 and SKBR3 cell lines signified G2/M cell cycle arrest. Cleaved caspases 9 and 3 were detected in rfhSP-D-treated BT474 and SKBR3 cells, suggesting an involvement of the intrinsic apoptosis pathway. However, rfhSP-D-induced apoptosis was nullified in the presence of hyaluronic acid (HA) whose increased level in breast tumor microenvironment is associated with malignant tumor progression and invasion. rfhSP-D bound to solid-phase HA and promoted tumor cell proliferation. rfhSP-D-treated SKBR3 cells in the presence of HA showed decreased transcriptional levels of p53 when compared to cells treated with rfhSP-D only. Thus, HA appears to negate the anti-tumorigenic properties of rfhSP-D against HER2-overexpressing and triple-positive breast cancer cells.
Highlights
The immune surveillance of transformed cells by innate and adaptive immunity remains one of the targeted areas of research for developing therapeutic strategies [1, 2]
All three breast cancer cell lines (BT20, BT474, and SKBR3) were able to adhere to hyaluronic acid (HA), to recombinant fragment of human SP-D (rfhSP-D), and to HA-bound rfhSP-D. rfhSP-D enticed a greater cell adhesion when compared to HA alone or HA-bound rfhSP-D; all three cell lines bound to similar extent (Figure 5B)
We show that rfhSP-D binds to all breast cancer cell lines tested: BT20 (ER−/PR−/HER2−), BT474 (ER+/PR+/HER2+), and SKBR3 (ER−/PR−/HER2+)
Summary
The immune surveillance of transformed cells by innate and adaptive immunity remains one of the targeted areas of research for developing therapeutic strategies [1, 2]. Human surfactant protein D (SP-D) is a potent innate immune molecule found at pulmonary and non-pulmonary mucosal surfaces [5] It is a member of the collectin family that is involved in the clearance of pathogens and apoptotic/necrotic cells and in the modulation of inflammatory responses [6]. All three breast cancer cell lines (BT20, BT474, and SKBR3) were able to adhere to HA, to rfhSP-D, and to HA-bound rfhSP-D. The implication of HA–rfhSP-D interaction on apoptosis induction in breast cancer cells was investigated (Figure 6A). HA + rfhSP-D-treated breast cancer cells were stained with mouse anti- Ki-67 antibody to detect the percentage proliferation (Figure 6B). Addition of HA in rfhSP-D-treated SKBR3 cells resulted in ∼30% cell proliferation (Figure 6B), suggesting that HA negated pro-apoptotic effects of rfhSP-D in breast cancer cell lines. The purified SP-D was not able to induce apoptosis in BT474 cells (Figure 6D)
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