Manipulating Cav-1 Could Be Key to Treating Form of Breast Cancer

As dynamic energy producing organelles, mitochondria need to regularly divide and reconnect with one another to exchange DNA and other molecules needed to maintain a cell’s health. Also essential in keeping cells healthy is mitophagy, as it quickly isolates, degrades and removes damaged mitochondria from a cell. Damaged mitochondria leads to the growth of the unstable atoms free radicals that promote cell death, whereas highly energetic mitochondria that actively remove damaged organelles exhibit increased survival.

Triple negative breast cancer cells (TNBC) are exceptionally good at repairing damaged mitochondria, thereby enabling rapid growth and metastasis of the aggressive tumors. However, it also makes it difficult to treat this type of breast cancer. A unique signaling pathway essential for survival of aggressive metastatic breast cancer cells has been discovered in the laboratory of University of Illinois Cancer Center member Richard Minshall, and by targeting the expression of the membrane protein caveolin-1 or reducing its phosphorylation, mitochondria becomes unable to repair themselves and cellular health deteriorates, making them vulnerable to cancer killing drugs.

Minshall, professor of Anesthesiology and Pharmacology at the University of Illinois College of Medicine and a member of the Cancer Center’s Cancer Biology program, and Ying “Olivia” Jiang, who serves as first author on the study published in the journal Redox Biology, found that caveolin-1 (Cav-1) is a key regulator of mitochondrial dynamics and mitophagy. By directly interacting with two proteins – Drp1 and Mfn2 – responsible for mitochondrial fission/fusion dynamics, as well as mitophagy, it facilitates cancer survival and metastasis.

“When we reduced caveolin-1 expression or promoted its dephosphorylation, the two proteins were able to travel to mitochondria and promote fission and fusion dynamics and mitophagy. When phosphorylated, caveolin-1 sequesters Mfn2 and Drp1 and prevents their translocation to the mitochondria, thereby blocking the repair of damaged mitochondria. Thus, TNBCs can potentially be made more vulnerable to cancer killing therapies such as chemotherapeutics by regulating Cav-1 phosphorylation, which we are now actively pursuing in collaboration with Saverio Gentile in the Department of Medicine and the Cancer Center’s Translational Oncology program,” Minshall said.

Triple-negative breast cancer accounts for about 10% to 15% of all breast cancers. The term refers to the fact the cancer cells don’t have estrogen or progesterone receptors (ER or PR) and also don’t make any or too much of the protein called HER2. TNBCs tend to be more common in women younger than age 40, who are Black, or who have a BRCA1 mutation. The disease differs from other types of invasive breast cancer in that it tends to grow and spread faster, has fewer treatment options, and tends to have a worse prognosis, according to the American Cancer Society.

Jiang analyzed more than 30,000 individual mitochondria with an image processing program and categorized them into different length groups. Quantification revealed that subpopulations with the shortest and longest length both increased, whereas the number of mitochondria in the intermediate group decreased in Cav-1 depleted cells. The average length was calculated by dividing the total length by the number of mitochondria. Mitochondrial length following Cav-1 knockdown was reduced by 15% compared to the control group.

The specific role of Cav-1 in cancer has long been debated, but the most recent research may prove to be critical during cancer chemotherapy, Jiang said.

“Our data suggests that Cav-1 phosphorylation, by inhibiting mitophagy, may facilitate resistance of triple negative breast cancer cells to chemotherapy, and that maximal cytotoxic effects of drugs, as well as immunotherapy, might be realized by manipulating Cav-1 phosphorylation or expression,” Jiang said. “Reducing Cav-1 expression or inhibition of phosphorylation may therefore affect cell survival by increasing mitochondrial dynamics and mitophagy.”

Assisting Jiang and Minshall were Sarah Krantz, Hirushi Gunasekara, Young-Mee Kim, Adrianna Zimnicka, Misuk Bae, Ke Ma, Peter Toth, Ying Hu, all of UIC; Saverio Gentile and Jalees Rehman, UIC and the University of Illinois Cancer Center; Xiang Qin, Shun Xi and Yiyao Liu, the University of Electronic Science and Technology of China; Ayesha Shajahan-Haq, Georgetown University; Hemal Patel, University of California, San Diego; and Marcelo Bonini, Northwestern University.

The research was supported by National Institutes of Health grants R01-HL142636, R01-HL126516, P01-HL60678, T32-HL007829, T32-HL139439, and National Natural Science Foundation of China grants 31800780 and U19A2006.

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