海角社区 BE, ChE Team Study Drug Resistance in ER+ Breast Cancer Cells
October 27, 2021
BATON ROUGE, LA 鈥� Estrogen receptor-positive (ER+) breast cancer is the most common
type of breast cancer diagnosed today. When someone has ER+ breast cancer, the cancer
cells鈥� growth is facilitated by the estrogen receptor. In breast cancer, hormone receptors
(proteins located in and around breast cells) signal cancerous cells to grow uncontrollably,
resulting in a tumor.
According to the American Cancer Society, two out of three breast cancer cases are hormone receptor-positive with 60-70 percent of those cases being ER+. Targeted therapies exist for ER+ breast cancer, however, nearly half of those patients will become resistant to endocrine therapy. Thanks to a $140,000 grant from the National Cancer Institute, two 海角社区 professors and their students are researching what causes this resistance to treatment.
海角社区 Biological Engineering Assistant Professor Elizabeth Martin, who is the principal investigator on the NCI research project, says that while ER+ breast cancer is more likely to respond to endocrine therapy, 40 percent of ER+ patients become resistant to this treatment.
Endocrine therapy directly targets the estrogen receptor unlike chemotherapy, which can target proliferating cells in the body, including healthy cells.
鈥淓ither patients already had resistance to the endocrine treatment or acquired it over time,鈥� Martin said. 鈥淯nfortunately, when there is resistance in the ER+ cells, it can be seen after the cancer cells have metastasized and moved on to another organ.鈥�
海角社区 Chemical Engineering Associate Professor Adam Melvin, who serves as the co-PI on the project, says that they are not so much studying resistance at the primary site, but the journey from point A to point B as the cancer cell metastasizes or moves to another spot in the body.
鈥淭he hypothesis we have is that the cancer cells pick up mutations [so that they go] from being susceptible to endocrine therapy to being resistant,鈥� he said. 鈥淗ow does it become resistant?鈥�
One thing that could make them change, Melvin added, is fluid shear stress. This occurs as the cell moves through the vasculature, putting pressure on the cell. Prolonged exposure to this pressure can cause the cell to mutate, which can make it stronger. Melvin compares it to someone going down a waterslide where the fluid velocity of the water puts more pressure on the body.
鈥淲e think the fluid velocity pushing on that cell induces mutations, and we think that stressful environment on the cell is causing it to develop this resistance,鈥� he said.
Martin says the ultimate goal of this research is to understand how to resensitize cancer cells to endocrine therapy so that patients don鈥檛 need to move to treatments like chemotherapy.
鈥淢etastasizing cancer cells should all consistently experience fluid shear stress,鈥� she said. 鈥淚f they鈥檙e all experiencing it, it should be activating the same intracellular pathways in the cells. When the cells get to the final site and don鈥檛 respond to endocrine therapy, you can use whatever pathway shear stress is activating as an additional target to resensitize the cells to endocrine therapy. So, instead of saying, 鈥榥ow you need chemotherapy,鈥� we now know what鈥檚 being activated in the cells as they鈥檙e metastasizing. So, here are options to resensitize cancer cells to endocrine therapy.鈥�
海角社区 ChE graduate student Braulio Ortega Quesada of San Pedro, Costa Rica, and 海角社区
BE graduate student Jonathan Cuccia of Meraux, La., work under Melvin and Martin and
are stressing out the ER+ cells on a micron-scale waterslide, as well as analyzing
them in groups and individually at the end to see how the cells differ from one another.
They run the breast cancer cells through a microfluidic device that shears the cells and then traps them in an array that can hold up to 7,000 cells, which can be stained for changes in protein expression. While Quesada analyzes single cells, Cuccia looks at millions of cells at a time.
鈥淭he microfluidic device serves as a channel that imparts the same relative amounts of fluid shear stress that metastasizing cancer cells would experience in your vasculature,鈥� Cuccia said. 鈥淲e don鈥檛 actually know if the fluid shear stress causes the cells to mutate. That鈥檚 what we鈥檙e looking for. What鈥檚 different about cancer cells is that in the primary site, ER+ cancer can change and morph into ER- in a metastatic state. We don鈥檛 know exactly where along the metastatic cascade that occurs, so we鈥檙e investigating its journey through the blood vessels to see if that鈥檚 where the environmental stimuli caused by the shear stress activates them.鈥�
Part of Quesada and Cuccia鈥檚 research entails taking photos of the cells under a microscope, which can be time-consuming in the lab. In order to help decrease the amount of time spent taking photos, Martin and Melvin have assigned a biological engineering senior design team to create an automated image-capturing system. The six-person team was divided into a hardware team led by 海角社区 BE senior Morgan Doyle of Madisonville, La., and a software team led by 海角社区 ChE senior Adam Langlois of Meraux, La. Other team members include Jacob Chaisson of Houma, La., Logan Brou of Port Allen, La., Alejandra Ham of Slidell, La., and Sarah Jimenez of Ponchatoula, La.
鈥淲e鈥檙e editing the microscope [so that it] can do automated image-capturing that will allow more time for the grad students to work on other aspects of the project,鈥� Langlois said. 鈥淩ight now, Braulio must take photos of the cell groups (3,000 total cells), which takes an hour. The objective for the automated system will take less time, but exactly how long is not known yet.鈥�
鈥淚鈥檝e been doing breast cancer research in Dr. Martin鈥檚 lab for nearly two years, so for me, this is a really cool project, and it鈥檚 great knowing that what we鈥檙e doing is going to help the grad students progress their research at a faster pace,鈥� Doyle said.
So far, Quesada and Cuccia are seeing positive results in their labs, which should give hope to the thousands of ER+ breast cancer patients who are unresponsive to endocrine therapy at metastatic sites.
鈥淲e鈥檝e already seen some pretty promising things that have us excited,鈥� Cuccia said. 鈥淲e鈥檙e looking forward to where this goes in the future.鈥�
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