SARS-CoV-2 infects breast cancer cells via Estrogen Receptor

And the Tuberculosis question

I had a completely different article in mind to publish today, but alas sometimes fate laughs at your face, I will publish it soon enough, it is one of the AIDA, where I share mostly positive articles that don’t fit “anywhere else”.

First, much-needed context, which you can find as far back as 2022.

Spike protein S2 enhances amyloid-β production

My path to uncover and understand the complexity of SARS-CoV-2 contributing to, among other diseases, neurodegeneration, inevitably led me to the Kynurenine Pathway, the metabolic pathway responsible for the use of Tryptophan for “cell energy” among many immunomodulatory effects. At the time a “sleeper” paper was published, a paper not covered by many, and criticized by many scientists.

There the authors found and proposed that the S2 part of the Spike Protein binds to Estrogen Receptor Alpha (ER-a from here on). Estrogen receptors are present in many immune cells, such as CD4, CD8, it directly affect the Kynurenine Pathway, this receptor also plays an underappreciated role in neurodegeneration. It also plays a significant role in protection against endotoxin-related damage, it regulates the expression of Galectin-3 too.

The endocrine (hormonal) aspect of SARS-CoV-2 is highly complex. But there is another assortment of pathology these receptors play a complex role. Cancer.

"My synapses are not the same" and post-mRNA cancer increase

In April of this year, I wrote about a paper from Japan, in which the authors found a significant increase in ER-a and attributed this to the mRNA-LNP vaccination, rather than the Covid infection. And here we are, I will try to make it short and to the point.

Impact of in vitro SARS-CoV-2 infection on breast cancer cells

The pandemic of coronavirus disease 19 (COVID-19), caused by severe respiratory syndrome coronavirus 2 (SARS-CoV-2), had severe repercussions for breast cancer patients. Increasing evidence indicates that SARS-CoV-2 infection may directly impact breast cancer biology, but the effects of SARS-CoV-2 on breast tumor cells are still unknown. Here, we analyzed the molecular events occurring in the MCF7, MDA-MB-231 and HCC1937 breast cancer cell lines, representative of the luminal A, basal B/claudin-low and basal A subtypes, respectively, upon SARS-CoV-2 infection. Viral replication was monitored over time, and gene expression profiling was conducted. We found that MCF7 cells were the most permissive to viral replication. Treatment of MCF7 cells with Tamoxifen reduced the SARS-CoV-2 replication rate, suggesting an involvement of the estrogen receptor in sustaining virus replication in malignant cells. Interestingly, a metagene signature based on genes upregulated by SARS-CoV-2 infection in all three cell lines distinguished a subgroup of premenopausal luminal A breast cancer patients with a poor prognosis. As SARS-CoV-2 still spreads among the population, it is essential to understand the impact of SARS-CoV-2 infection on breast cancer, particularly in premenopausal patients diagnosed with the luminal A subtype, and to assess the long-term impact of COVID-19 on breast cancer outcomes.

Since there is little research on the impact of SARS-CoV-2 in specific types of cancer, therefore in specific cancer cell lines, the authors used 3 breast cancer cells here, representing each a subtype of breast cancer and each subtype has unique characteristics, this is why treating (and understanding) cancer is so complex. I often described it as paradoxical.

Each of these cell types responded differently to changes, such as blocking ACE2 reduced the viral replication in the MCF7 cells, but not in the other two. They subsequentially monitored the replication of the virus at different times in each cell line, and in the MDA and HCC it peaks at 24 hours and decreased over time, but in the MFC7 cells, it remained stable up to 3 days, and greatly increased from day 3 to 7.

The authors also observed a change in gene activity, with certain lines (MDA-MB) showing significant changes in gene activity shortly after infection. The researchers were able to create a SARS-CoV-2 Metagene, basically, a group of genes that were affected by the virus, and this metagene framework could predict poor outcomes in premenopausal women with luminal A breast cancer.

Lastly, they attempted to replicate what the authors referred to at the start of this article, SARS-CoV-2 interaction or the effects of the presence of Estrogen Receptor Alpha. And that is what they found, when the researchers treated MCF7 cells with Tamoxifen, a drug that blocks the estrogen receptor, they saw a reduction in the virus’s ability to replicate and a mild increase in senescence, also referred to as zombie cells, when they can’t divide or replicate.

This occurs in response to the viral infection, in response to cellular damage, and serves as a dual-edge protective mechanism to fight the virus infection. On one hand, this “zombification” of cells in response to SARS-CoV-2 infection and treatment by using the estrogen modulator protects against the viral spread, yet, senescence is a known factor in human disease especially cancer, so it can produce more inflammation which in turn “feeds” the cancer.

However, our data can have important clinical relevance. Since we found that the estrogen receptor breast cancer cell line MCF7 was the most permissive to virus replication, it would be possible to imagine a scenario in which estrogen receptor positive breast tumors may act as a sort of SARS-CoV-2 reservoir that can continuously supplies new viral particles thus exacerbating COVID-19 aggressiveness and the consequences associated to this disease.

It is cancer “type” dependent but the virus can exploit the Estrogen Receptor in breast tumors that possess these receptors to form a viral reservoir that can continuously supply new viral particles. This creates a very complex immunological situation in which it can both make the treatment worse, accelerate the progress of the cancer, and also degrade an already frail immune system.

Persistent SARS-COV-2 infection in cancer patients is not a new “thing”, the debate often resided between “a long-lasting fiction x potential reservoir”, now with further evidence of the interaction of the virus itself, not purified Spike Protein as in the previous paper, with the Estrogen Receptor, we can extrapolate that not only virus is persisting and creating a reservoir in different tissues, but Spike is also present in tumors, specifically ER-a ones. This opens up the avenue for me to finally spend time on my “Persistent, reservoir SARS-CoV-2” article.

And either to mine or anyone else’s future reference. Reminder, this is a nuclear receptor.

ERα, thus, not only controls the transcription of many genes (Frasor et al., 2003) but also binds many mRNAs to regulate post-transcriptional RNA processing and metabolism. Xu et al. also demonstrate a critical role of RNA binding by ERα in contributing to breast cancer progression and cancer cell survival

And just to add something else.


Back in 2021, when I and my mentor-friend were basically reverse engineering the mRNA vaccines to attempt to make sense of it all, and help people avoid substantial damage, each of us had our perspective. My angle was trying to understand how toxins, especially Endotoxins and biofilms fit into the picture, the only variable that would explain most of it. Mentor-friend ?

Among its many highly ahead of its time observations, that among many other potential uses, SARS-CoV-2 was a work-in-progress towards a Tuberculosis vaccine, since China suffers one of the heaviest Tb burdens in the world. Well, I guess “suffered” is the correct term

Source

• Globally, the number of TB patients newly diagnosed and reported had a large drop in 2020

• Changes in tuberculosis burden and its associated risk factors in Guizhou Province of China, experienced the biggest changes in…2020

• The results showed that the incidence of tuberculosis cases in Shantou, China decreased significantly (p < 0.05) during the pandemic as compared to that prior to the pandemic.

• The number of tuberculosis infections in China declined to 52 cases per 100,000 population in 2022. This marks the lowest number of tuberculosis infections during the observed period.

This is biology, and biology is nothing but highly complex, but it will be very interesting to see how certain diseases fluctuate and change their behavior and evolution in China and around the world as time goes on. I wrote this section out of “curious tidbit” and in case said friend ever reads this. You were right, and ahead, as you usually were.


I am not an academic, so your support is greatly appreciated. Thank you !