Oncogenic role of an uncharacterized cold-induced zinc finger protein 726 in breast cancer.

The unobtrusive cold environmental temperature can be linked to the development of cancer. This study, for the first time, envisaged cold stress-mediated induction of a zinc finger protein 726 (ZNF726) in breast cancer. However, the role of ZNF726 in tumorigenesis has not been defined. This study investigated the putative role of ZNF726 in breast cancer tumorigenic potency. Gene expression analysis using multifactorial cancer databases predicted overexpression of ZNF726 in various cancers, including breast cancer. Experimental observations found that malignant breast tissues and highly aggressive MDA-MB-231 cells showed an elevated ZNF726 expression as compared to benign and luminal A type (MCF-7), respectively. Furthermore, ZNF726 silencing decreased breast cancer cell proliferation, epithelial-mesenchymal transition, and invasion accompanied by the inhibition of colony-forming ability. Concordantly, ZNF726 overexpression significantly demonstrated opposite outcomes than ZNF726 knockdown. Taken together, our findings propose cold-inducible ZNF726 as a functional oncogene demonstrating its prominent role in facilitating breast tumorigenesis. An inverse correlation between environmental temperature and total serum cholesterol was observed in the previous study. Furthermore, experimental outcomes illustrate that cold stress elevated cholesterol content hinting at the involvement of the cholesterol regulatory pathway in cold-induced ZNF726 gene regulation. This observation was bolstered by a positive correlation between the expression of cholesterol-regulatory genes and ZNF726. Exogenous cholesterol treatment elevated ZNF726 transcript levels while knockdown of ZNF726 decreased the cholesterol content via downregulating various cholesterol regulatory gene expressions (e.g., SREBF1/2, HMGCoR, LDLR). Moreover, an underlying mechanism supporting cold-driven tumorigenesis is proposed through interdependent regulation of cholesterol regulatory pathway and cold-inducible ZNF726 expression.

Docosahexaenoic Acid (DHA) Inhibits Bone Morphogenetic Protein-2 (BMP-2) Elevated Osteoblast Potential of Metastatic Breast Cancer (MDA-MB-231) Cells in Mammary Microcalcification.

Microcalcification seems to be an assurance signature for the prediction of breast cancer malignancy. However, neither systematic study for deciphering the molecular mechanism of mammary microcalcification has yet been conducted, nor a mechanistic study has been performed to find out its prevention. Thus, this study firstly aimed at determining if malignant breast tissues/metastatic breast cancer cells exhibit elevated intrinsic osteoblast-like potential responsible for driving the pathological microcalcification in breast tumors. Here, tumor sample analysis showed higher levels of various osteogenic genes (e.g., Runx2, osterix), and increased ALP activity and calcification in malignant breast tissues when compared to benign tissues, indicating the existence of elevated osteoblast-like potential in malignant breast tissues as compared to benign tissues. Similarly, cell culture study found that metastatic MDA-MB-231 cells acquired a higher osteoblast-like potential as compared to less metastatic breast cancer MCF-7 cells. It was also noticed that osteoinducer bone morphogenetic protein 2 (BMP-2) increased osteoblast-like differentiation and calcification potential in breast cancer cells. Moreover, omega-3 fatty acid docosahexaenoic acid (DHA) showed an inhibitory effect on BMP-2 induced osteoblast-like potential presumably by abrogating BMP signaling. Thus, this study for the first time unraveled that DHA may mitigate microcalcification by blocking osteoblast-like potential of breast cancer cells.

Metformin exhibited anticancer activity by lowering cellular cholesterol content in breast cancer cells.

Metformin, a widely prescribed anti-diabetic drug, shows anticancer activity in various cancer types. Few studies documented that there was a decreased level of LDL and total cholesterol in blood serum of metformin users. Based on these views, this study aimed to determine if metformin exhibits anticancer activity by alleviating cholesterol level in cancer cells. The present study found that treatment of breast cancer MDA-MB-231 cells with metformin significantly decreased cholesterol content with concomitant inhibition of various cholesterol regulatory genes (e.g., HMGCoR, LDLR and SREBP1). Metformin decreased cell viability, migration and stemness in metastatic MDA-MB-231 cells. Similarly, metformin treatment suppressed expressions of anti-apoptotic genes BCL2 and Bcl-xL, and mesenchymal genes vimentin, N-cadherin, Zeb1 and Zeb2 with simultaneous enhancement of apoptotic caspase 3 and Bax, and epithelial genes E-cadherin and keratin 19 expressions, confirming an inhibitory effect of metformin in tumorigenesis. Similar to metformin, depletion of cholesterol by methyl beta cyclodextrin (MBCD) diminished cell viability, migration, EMT and stemness in breast cancer cells. Moreover, metformin-inhibited cell viability, migration, colony and sphere formations were reversed back by cholesterol treatment. Similarly, cholesterol treatment inverted metformin-reduced several gene expressions (e.g., Bcl-xL, BCL2, Zeb1, vimentin, and BMI-1). Additionally, zymography data demonstrated that cholesterol upregulated metformin-suppressed MMP activity. These findings suggested that metformin revealed anticancer activity by lowering of cholesterol content in breast cancer cells. Thus, this study, for the first time, unravelled this additional mechanism of metformin-mediated anticancer activity.